The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index; 13 of the 46 sources its claims cite were checked for support.
Perineuronal nets protect fast-spiking interneurons against oxidative stress
Open accessAbstract
A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
In mice with genetically impaired glutathione synthesis, mature perineuronal nets around parvalbumin-positive fast-spiking interneurons limited oxidative damage and preserved local rhythmic synchrony. Removing these nets made the cells more vulnerable, while severe oxidative stress also degraded the nets themselves.
Key findings
- At postnatal day 90, Gclm knockout mice had higher anterior cingulate oxidative DNA damage than wild-type mice (8-oxo-dG intensity 2.16 ± 0.18 vs. 1.12 ± 0.66; 4 mice per group; P = 0.02), but parvalbumin cell and perineuronal net numbers were still comparable. By P180, knockout mice had fewer parvalbumin-immunoreactive cells, unchanged WFA-labeled nets, and a higher proportion of remaining parvalbumin cells wrapped by nets, alongside weaker β and γ oscillations.
- The dopamine reuptake inhibitor GBR increased oxidative stress in Gclm knockout mice at both P20 and P90, with stronger labeling at P20; it reduced parvalbumin cell numbers at P20 but not P90. In P90 knockout mice after GBR, per-cell oxidative stress was inversely correlated with the density of surrounding WFA-labeled perineuronal nets.
- Unilateral chondroitinase ABC degradation of mature nets in P90 Gclm knockout mice made GBR-treated animals lose parvalbumin cells and show higher 8-oxo-dG labeling on the degraded side; calbindin and calretinin cells were unaffected. Oscillation power showed a significant interaction between net status and GBR treatment (P = 0.039).
- Mice with parvalbumin-cell-specific deletion of Gclc, causing severe cell-autonomous redox dysregulation, had more 8-oxo-dG within parvalbumin cells and fewer parvalbumin cells and WFA-labeled nets; about 70% of PV-Cre-positive cells lacked Gclc mRNA in cortex at 2 months.
Methods
- Used Gclm knockout mice with low brain glutathione and conditional PV-Gclc knockout mice lacking glutathione synthesis selectively in parvalbumin cells; wild-type or PV-Cre controls were compared.
- Applied additional oxidative challenge with daily GBR injections from P10–P20 or P80–P90, and degraded perineuronal nets by unilateral intracortical chondroitinase ABC injection into anterior cingulate cortex with contralateral vehicle sham.
- Measured 8-oxo-dG, parvalbumin, calbindin, calretinin, and WFA-labeled nets by immunohistochemistry and stereology; recorded carbachol/kainic acid/quinpirole-induced β and γ oscillations in slices; analyzed with ANOVA, Dunnett tests, Pearson correlation, and multivariate analysis.
Limitations
- The paper states that other factors besides immature perineuronal nets may contribute to the high vulnerability of parvalbumin cells during maturation, and that in the PV-Gclc model it remains unclear whether net loss precedes loss of parvalbumin expression or follows cell dysfunction or degeneration.
- Evident from the text: findings come from mouse models and slice physiology, with some groups having small sample sizes (for example, 4–7 mice in several experiments), and the protective relationship between net density and oxidative stress is correlational in the GBR-treated P90 knockout analysis.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
55 Own result · 29 Own interpretation · 15 No full text of the sources · 8 Sources not found · 6 Couldn’t confirm · 4 Partly supported · 3 Own method · 1 Supported · 1 Not checked yet · accuracy not yet measured
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).”
What the sources say
- Could not verifycites [3] 3. Sohal VS, Zhang F, Yizhar O, Deisseroth K (2009) Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459(7247):698-702. sourceExperimental — accuracy not yet measured
The passages on PV interneurons and gamma rhythms (section labeled Abstract; page unavailable) identify PV cells as fast-spiking, but do not address metabolic demand, mitochondrial density, or oxidative-stress sensitivity. Searches for those terms and for the comparison with calretinin and calbindin cells found no passage supporting the attributed causal claim. (LLM, conf=0.72)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Furthermore, the antioxidant N-acetylcysteine prevents the GBRinduced PV-cell defect in Gclm KO mice (3).”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Results
What the sources say
- Could not verifycites [3] 3. Sohal VS, Zhang F, Yizhar O, Deisseroth K (2009) Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459(7247):698-702. sourceExperimental — accuracy not yet measured
The paper’s Abstract and Methods Summary describe optogenetic experiments in PV::Cre mice, not antioxidant treatment in Gclm knockout mice. Searches for N-acetylcysteine, GBR, Gclm knockout mice, and oxidative stress found no passage addressing the claimed prevention of a PV-cell defect; page numbers were unavailable. (LLM, conf=0.78)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Across multiple neuropsychiatric disorders, including autism, schizophrenia, and bipolar disorder, the developmental gene expression program in PV cells is instead immature (54).”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
What the sources say
- Partly supportedcites [54] 54. Beurdeley M, et al. (2012) Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex. J Neurosci 32(27):9429-9437. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) proposes that therapies targeting Otx2 transfer into PV circuits might apply to autism spectrum disorders and schizophrenia, which it describes as having a similar cellular etiology. It does not report an immature developmental gene-expression program in PV cells in those disorders, and it does not mention bipolar disorder in this context. (LLM, conf=0.82)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“ROS is known to break down two PNN components, hyaluronan and chondroitin sulfate (47).”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
What the sources say
- Could not verifycites [47] 47. Cañas N, et al. (2007) Chondroitin sulfate protects SH-SY5Y cells from oxidative stress by inducing heme oxygenase-1 via phosphatidylinositol 3-kinase/Akt. J Pharmacol Exp Ther 323(3):946-953. sourceExperimental — accuracy not yet measured
The Introduction says ROS damage cells through lipid destruction and DNA cleavage, while the Discussion describes hyaluronic acid and chondroitin sulfate as antioxidants. Neither passage says ROS break down those two perineuronal-net components. Searches for their degradation by ROS or free radicals found no such statement in our copy; page numbers were not provided. (LLM, conf=0.73)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Given the pivotal role of PV cells and PNNs in regulating the onset and closure of brain plasticity (52,57), oxidative stress may contribute to the slow emergence of psychoses by mistiming key windows of brain development.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
What the sources say
- Partly supportedcites [52] 52. Pantazopoulos H, Woo TU, Lim MP, Lange N, Berretta S (2010) Extracellular matrix- glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 67(2):155-166. sourceExperimental — accuracy not yet measured
The Comments section (page unavailable) says PNN organization controls the closure of critical periods and suggests that disrupted PNN formation in schizophrenia may affect neural circuitry. The paper does not establish a role in the onset of those periods. The oxidative-stress proposal follows the citations in the citing sentence and is not attributed to this source. (LLM, conf=0.83)
- Could not verifycites [57] 57. McEwen BS (2012) The ever-changing brain: Cellular and molecular mechanisms for the effects of stressful experiences. Dev Neurobiol 72(6):878-890. sourceExperimental — accuracy not yet measured
The “Initial evidence for adult brain plasticity” section discusses developmental critical periods, but not their mistiming by oxidative stress or a resulting emergence of psychoses. Searches of our copy for oxidative stress, psychosis, and related terms found no passage addressing that proposed link; pages were not supplied. (LLM, conf=0.75)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.”
- Also stated in: § PNNs Are Themselves Sensitive to Excessive Redox Dysregulation. Although the additional oxidative stress generated by GBR did not affect PV immunoreactivity in P90 Gclm KO mice (Fig. 2B), it led to an overall decrease in WFA labeling around PV cells (Fig. 3).This indicates that although PNNs limit oxidative stress and protect PV cells, they are also by themselves sensitive to excess amounts of oxidative stress.We then investigated the effects of a cell-autonomous redox dysregulation on PV immunoreactivity and WFA-labeled PNNs.We generated mice whose PV cells were fully incapable of synthesizing GSH by a restricted deletion of the gene coding for the catalytic subunit of glutamate cysteine ligase (GCLC), only in PV cells.PV-Gclc KO mice showed a progressive GCLC deletion in PV-expressing cells, with ∼70% of PV-Cre(+) cells displaying no Gclc mRNA in the cerebral cortex of 2-mo-old animals.These conditional KO mice displayed a much stronger 8-oxo-dG labeling within PV cells compared with PV-Gclc WT mice (Fig. 4 A and B) or Gclm KO mice (Fig. S4).Under such severe cell-autonomous redox dysregulation, significantly fewer PV immunoreactive cells and WFA-labeled PNNs were observed (Fig. 4 C and D).In cortical layers enriched in PV cells, some cells displayed strong 8-oxo-dG labeling, although they were neither PV immunoreactive (Fig. 4A) nor enwrapped by WFA-labeled PNNs.These may represent PV cells that had already lost PV immunoreactivity.However, in this model, it remains unclear whether the loss of WFA-labeled PNNs precedes the loss of PV expression or whether it is the consequence of PV-cell dysfunction or degeneration. Degradation of Mature PNNs Renders PV Cells More Susceptible to Oxidative Stress.To substantiate whether mature PNNs play a protective role, we stripped them off the ACC of young adult (P90) Gclm KO mice and monitored PV-cell susceptibility to oxidative stress, using GBR.The chondroitinase ABC (ChABC) enzyme was locally injected into one ACC, and the contralateral side received a vehicle (sham).ChABC injection efficiently degraded PNNs unilaterally, as verified 2 d postinjection by the absence of WFA labeling in the treated ACC (Fig. S5).After ChABC injection, mice were further treated for 11 consecutive days with either GBR or a vehicle (PBS) and then killed (Fig. 5D).In both PBS-treated (n = 5) and GBR-treated (n = 7) mice, WFA labeling in the ChABC-injected ACC was faint and significantly weaker than in sham ACC (P < 0.001; Fig. 5A).However, only GBR caused a significant decrease in the number of PV immunoreactive cells in the ChABC-injected ACC compared with the contralateral side (Fig. 5B).The 8-oxo-dG labeling after GBR treatment was likewise significantly higher in ChABC-injected than in sham ACC (Fig. 5C).PNN degradation did not, however, affect the number of calbindin-and calretininimmunoreactive cells when subjected to GBR-induced oxidative stress (Fig. S6).This demonstrates that mature PNNs specifically protect PV cells from additional oxidative stress. Finally, we functionally assessed whether PNN degradation rendered local PV-cell networks vulnerable to further oxidative stress.Fast rhythmic oscillations reflecting neuronal synchronization were clearly altered in slices of ChABC-injected ACC from the P90 GBR-treated Gclm KO mice [significant interaction between treatment (PBS vs. GBR) and PNN status (ChABC vs. contralateral sham), multivariate analysis; P = 0.039].In control PBS-treated Gclm KO mice, the power of oscillations (induced by coapplication of carbachol, kainic acid, and quinpirole) tended to be stronger in the ChABC-injected side compared with contralateral sham ACC (Fig. 5E).Instead, in GBR-treated Gclm KO mice, the power of oscillations tended to be weaker in the ChABC-injected side compared with sham ACC (Fig. 5F).Thus, a lack of PNNs favors β/γ oscillatory power, which is then weakened during oxidative stress challenge, consistent with the reduced number of PV immunoreactive cells under the latter condition (Fig. 5B). · plain
“PNNs Are Themselves Sensitive to Excessive Redox Dysregulation.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § PNNs Are Themselves Sensitive to Excessive Redox Dysregulation. Although the additional oxidative stress generated by GBR did not affect PV immunoreactivity in P90 Gclm KO mice (Fig. 2B), it led to an overall decrease in WFA labeling around PV cells (Fig. 3).This indicates that although PNNs limit oxidative stress and protect PV cells, they are also by themselves sensitive to excess amounts of oxidative stress.We then investigated the effects of a cell-autonomous redox dysregulation on PV immunoreactivity and WFA-labeled PNNs.We generated mice whose PV cells were fully incapable of synthesizing GSH by a restricted deletion of the gene coding for the catalytic subunit of glutamate cysteine ligase (GCLC), only in PV cells.PV-Gclc KO mice showed a progressive GCLC deletion in PV-expressing cells, with ∼70% of PV-Cre(+) cells displaying no Gclc mRNA in the cerebral cortex of 2-mo-old animals.These conditional KO mice displayed a much stronger 8-oxo-dG labeling within PV cells compared with PV-Gclc WT mice (Fig. 4 A and B) or Gclm KO mice (Fig. S4).Under such severe cell-autonomous redox dysregulation, significantly fewer PV immunoreactive cells and WFA-labeled PNNs were observed (Fig. 4 C and D).In cortical layers enriched in PV cells, some cells displayed strong 8-oxo-dG labeling, although they were neither PV immunoreactive (Fig. 4A) nor enwrapped by WFA-labeled PNNs.These may represent PV cells that had already lost PV immunoreactivity.However, in this model, it remains unclear whether the loss of WFA-labeled PNNs precedes the loss of PV expression or whether it is the consequence of PV-cell dysfunction or degeneration. Degradation of Mature PNNs Renders PV Cells More Susceptible to Oxidative Stress.To substantiate whether mature PNNs play a protective role, we stripped them off the ACC of young adult (P90) Gclm KO mice and monitored PV-cell susceptibility to oxidative stress, using GBR.The chondroitinase ABC (ChABC) enzyme was locally injected into one ACC, and the contralateral side received a vehicle (sham).ChABC injection efficiently degraded PNNs unilaterally, as verified 2 d postinjection by the absence of WFA labeling in the treated ACC (Fig. S5).After ChABC injection, mice were further treated for 11 consecutive days with either GBR or a vehicle (PBS) and then killed (Fig. 5D).In both PBS-treated (n = 5) and GBR-treated (n = 7) mice, WFA labeling in the ChABC-injected ACC was faint and significantly weaker than in sham ACC (P < 0.001; Fig. 5A).However, only GBR caused a significant decrease in the number of PV immunoreactive cells in the ChABC-injected ACC compared with the contralateral side (Fig. 5B).The 8-oxo-dG labeling after GBR treatment was likewise significantly higher in ChABC-injected than in sham ACC (Fig. 5C).PNN degradation did not, however, affect the number of calbindin-and calretininimmunoreactive cells when subjected to GBR-induced oxidative stress (Fig. S6).This demonstrates that mature PNNs specifically protect PV cells from additional oxidative stress. Finally, we functionally assessed whether PNN degradation rendered local PV-cell networks vulnerable to further oxidative stress.Fast rhythmic oscillations reflecting neuronal synchronization were clearly altered in slices of ChABC-injected ACC from the P90 GBR-treated Gclm KO mice [significant interaction between treatment (PBS vs. GBR) and PNN status (ChABC vs. contralateral sham), multivariate analysis; P = 0.039].In control PBS-treated Gclm KO mice, the power of oscillations (induced by coapplication of carbachol, kainic acid, and quinpirole) tended to be stronger in the ChABC-injected side compared with contralateral sham ACC (Fig. 5E).Instead, in GBR-treated Gclm KO mice, the power of oscillations tended to be weaker in the ChABC-injected side compared with sham ACC (Fig. 5F).Thus, a lack of PNNs favors β/γ oscillatory power, which is then weakened during oxidative stress challenge, consistent with the reduced number of PV immunoreactive cells under the latter condition (Fig. 5B). · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.”
- Also stated in: § Results · plain
“Immature PV Cells Bearing Less-Condensed PNNs Are More Vulnerable to Oxidative Stress.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Results · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.”
- Also stated in: § Results · plain
“The degree of oxidative stress per PV cell (8-oxo-dG labeling) varied with the PNN density (WFA labeling) surrounding it, yielding a significant inverse correlation (Fig. 2D).”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Results · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PNNs Are Themselves Sensitive to Excessive Redox Dysregulation.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > PNNs Are Themselves Sensitive to Excessive Redox Dysregulation. Although the additional oxidative stress generated by GBR did not affect PV immunoreactivity in P90 Gclm KO mice (Fig. 2B), it led to an overall decrease in WFA labeling around PV cells (Fig. 3).This indicates that although PNNs limit oxidative stress and protect PV cells, they are also by themselves sensitive to excess amounts of oxidative stress.We then investigated the effects of a cell-autonomous redox dysregulation on PV immunoreactivity and WFA-labeled PNNs.We generated mice whose PV cells were fully incapable of synthesizing GSH by a restricted deletion of the gene coding for the catalytic subunit of glutamate cysteine ligase (GCLC), only in PV cells.PV-Gclc KO mice showed a progressive GCLC deletion in PV-expressing cells, with ∼70% of PV-Cre(+) cells displaying no Gclc mRNA in the cerebral cortex of 2-mo-old animals.These conditional KO mice displayed a much stronger 8-oxo-dG labeling within PV cells compared with PV-Gclc WT mice (Fig. 4 A and B) or Gclm KO mice (Fig. S4).Under such severe cell-autonomous redox dysregulation, significantly fewer PV immunoreactive cells and WFA-labeled PNNs were observed (Fig. 4 C and D).In cortical layers enriched in PV cells, some cells displayed strong 8-oxo-dG labeling, although they were neither PV immunoreactive (Fig. 4A) nor enwrapped by WFA-labeled PNNs.These may represent PV cells that had already lost PV immunoreactivity.However, in this model, it remains unclear whether the loss of WFA-labeled PNNs precedes the loss of PV expression or whether it is the consequence of PV-cell dysfunction or degeneration. Degradation of Mature PNNs Renders PV Cells More Susceptible to Oxidative Stress.To substantiate whether mature PNNs play a protective role, we stripped them off the ACC of young adult (P90) Gclm KO mice and monitored PV-cell susceptibility to oxidative stress, using GBR.The chondroitinase ABC (ChABC) enzyme was locally injected into one ACC, and the contralateral side received a vehicle (sham).ChABC injection efficiently degraded PNNs unilaterally, as verified 2 d postinjection by the absence of WFA labeling in the treated ACC (Fig. S5).After ChABC injection, mice were further treated for 11 consecutive days with either GBR or a vehicle (PBS) and then killed (Fig. 5D).In both PBS-treated (n = 5) and GBR-treated (n = 7) mice, WFA labeling in the ChABC-injected ACC was faint and significantly weaker than in sham ACC (P < 0.001; Fig. 5A).However, only GBR caused a significant decrease in the number of PV immunoreactive cells in the ChABC-injected ACC compared with the contralateral side (Fig. 5B).The 8-oxo-dG labeling after GBR treatment was likewise significantly higher in ChABC-injected than in sham ACC (Fig. 5C).PNN degradation did not, however, affect the number of calbindin-and calretininimmunoreactive cells when subjected to GBR-induced oxidative stress (Fig. S6).This demonstrates that mature PNNs specifically protect PV cells from additional oxidative stress. Finally, we functionally assessed whether PNN degradation rendered local PV-cell networks vulnerable to further oxidative stress.Fast rhythmic oscillations reflecting neuronal synchronization were clearly altered in slices of ChABC-injected ACC from the P90 GBR-treated Gclm KO mice [significant interaction between treatment (PBS vs. GBR) and PNN status (ChABC vs. contralateral sham), multivariate analysis; P = 0.039].In control PBS-treated Gclm KO mice, the power of oscillations (induced by coapplication of carbachol, kainic acid, and quinpirole) tended to be stronger in the ChABC-injected side compared with contralateral sham ACC (Fig. 5E).Instead, in GBR-treated Gclm KO mice, the power of oscillations tended to be weaker in the ChABC-injected side compared with sham ACC (Fig. 5F).Thus, a lack of PNNs favors β/γ oscillatory power, which is then weakened during oxidative stress challenge, consistent with the reduced number of PV immunoreactive cells under the latter condition (Fig. 5B).
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Compared with WT mice, the ACC of young adult (postnatal day, P90) Gclm KO mice displayed significantly more oxidative stress, as revealed by the presence of 8-oxo-7,8dihydro-20-deoxyguanine (8-oxo-dG), a product of DNA oxidation [8-oxo-dG intensity (arbitrary unit, mean ± SD): 2.16 ± 0.18 (KO) vs. 1.12 ± 0.66 (WT); 4 mice each; P = 0.02].”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Results
plaincorrelationaln = 4 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 34
- Probably not a substantial claim. 13
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).”
What the sources say
- Not checked — no full text of the sourcecites [18] 18. Andreazza AC, et al. (2008) Oxidative stress markers in bipolar disorder: A meta- analysis. J Affect Disord 111(2-3):135-144. source
- Partly supportedcites [19] 19. Yao JK, Keshavan MS (2011) Antioxidants, redox signaling, and pathophysiology in schizophrenia: An integrative view. Antioxid Redox Signal 15(7):2011-2035. sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) reports reduced prefrontal brain GSH in schizophrenia and a genetic association involving the catalytic subunit of glutamate cysteine ligase. It does not establish an association with GCLM, the modifier subunit, or assess whether Gclm knockout mice are a valid animal model. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [22] 22. Wang JF, Shao L, Sun X, Young LT (2009) Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia. Bipolar Disord 11(5):523-529. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Traumatic injury, which causes a rapid and strong increase in superoxide production and oxidative stress (48), notably leads to a transient reduction of WFA-labeled PNNs rendering the damaged tissue permissive for axon sprouting (49).”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
What the sources say
- Supportedcites [48] 48. Pitts MW, et al. (2012) Deletion of selenoprotein P results in impaired function of parvalbumin interneurons and alterations in fear learning and sensorimotor gating. Neuroscience 208:58-68. source
This source is citation (48), attached to the increase in superoxide production and oxidative stress; citation (49) is attached to the WFA-labeled PNN and axon-sprouting claim. The Results section (page unavailable) reports elevated superoxide at 1 hour after TBI, and the Methodology/Principal Findings section (page unavailable) reports a rapid rise in NADPH oxidase activity and oxidative-stress damage. (LLM, conf=0.91)
- Supportedcites [49] 49. Rees MD, Hawkins CL, Davies MJ (2004) Hypochlorite and superoxide radicals can act synergistically to induce fragmentation of hyaluronan and chondroitin sulphates. Biochem J 381(Pt 1):175-184. source
The Results report that WFA-labeled perineuronal nets were markedly reduced around the contusion at 7 days and began to repopulate by 28 days. The Discussion says that reduced nets and associated CSPGs provide correlative evidence of a growth-permissive environment where axon sprouting occurs; it does not establish the reduction as the sole cause of sprouting. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Both specific interactions with sugar residues in the PNNs (52) or sulfation patterns (53) enable the persistent uptake of this factor, which in turn promotes PNN formation, suggesting a positive feedback loop for PV-cell maintenance.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
What the sources say
- Could not verifycites [52] 52. Pantazopoulos H, Woo TU, Lim MP, Lange N, Berretta S (2010) Extracellular matrix- glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 67(2):155-166. sourceExperimental — accuracy not yet measured
The Methods section (page not specified) describes a lectin binding to a sugar residue in CSPGs, and the Abstract > Conclusions (page not specified) discusses PNNs around parvalbumin-positive neurons. Neither passage addresses Otx2 uptake or a feedback loop; searches for Otx2, sugar-residue interactions and sulfation patterns found no passage establishing that mechanism. (LLM, conf=0.75)
- Not checked — no full text of the sourcecites [53] 53. Kähler AK, et al. (2011) Candidate gene analysis of the human natural killer-1 car- bohydrate pathway and perineuronal nets in schizophrenia: B3GAT2 is associated with disease risk and cortical surface area. Biol Psychiatry 69(1):90-96. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: PNNs control the accumulation of Otx2 within PV cells.
- Could not verify
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“In addition to reduced PV expression and abnormal expression of several pre-and postsynaptic markers associated with PV cells, a significant decrease in WFA-labeled PNNs has recently been reported in patients with schizophrenia (50), potentially reflecting oxidative stress and decreased levels of GSH.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
What the sources say
- Could not verifycites [50] 50. Zhang QG, et al. (2012) Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury. PLoS ONE 7(4):e34504. sourceExperimental — accuracy not yet measured
The Results section on oxidative damage reports increased oxidative-stress markers after traumatic brain injury in mice, not findings in patients with schizophrenia. Searches for WFA-labeled perineuronal nets, schizophrenia, and GSH found no passage addressing the claimed decrease or its proposed explanation. Page numbers were not available in our copy. (LLM, conf=0.75)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Selenoprotein deficiency likewise reduces the number of PV cells and impairs behaviors such as fear learning and sensorimotor gating in mice (46).”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
What the sources say
- Partly supportedcites [46] 46. Campo GM, et al. (2004) Reduction of DNA fragmentation and hydroxyl radical production by hyaluronic acid and chondroitin-4-sulphate in iron plus ascorbate- induced oxidative stress in fibroblast cultures. Free Radic Res 38(6):601-611. sourceExperimental — accuracy not yet measured
The Introduction reports that Sepp1-knockout mice had fewer PV interneurons in the inferior colliculus and impaired sensorimotor gating. Results §3.4 reports enhanced acquisition and delayed extinction of contextual fear memory. The claim is broader than the evidence: the study deleted selenoprotein P specifically, found reduced PV cells in a particular brain region, and did not find uniformly impaired fear learning. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Pantazopoulos et al. (50) reported that the reduction of WFA-labeled PNNs is accompanied by an increase of chondroitin sulfate proteoglycans within glial cells of patients with schizophrenia, suggesting a defect in the capacity of glial cells to excrete some of the PNN components.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
What the sources say
- Could not verifycites [50] 50. Zhang QG, et al. (2012) Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury. PLoS ONE 7(4):e34504. sourceExperimental — accuracy not yet measured
The Results section reports β-amyloid staining and microglia-like cells after traumatic brain injury in mice, not WFA-labeled perineuronal nets in patients with schizophrenia. Searches for WFA-labeled nets, chondroitin sulfate proteoglycans, schizophrenia, and Pantazopoulos found no passage addressing the attributed finding or proposed defect in glial excretion. No page number is available in our copy. (LLM, conf=0.76)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Could not verify
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the oxidative stress levels were similar in P90 and P180 Gclm KO mice, the ACC of P180 Gclm KO mice contained fewer PV immunoreactive cells (Fig. 1 A and B) compared with age-matched WT mice.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Under such severe cell-autonomous redox dysregulation, significantly fewer PV immunoreactive cells and WFA-labeled PNNs were observed (Fig. 4 C and D).”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > PNNs Are Themselves Sensitive to Excessive Redox Dysregulation. Although the additional oxidative stress generated by GBR did not affect PV immunoreactivity in P90 Gclm KO mice (Fig. 2B), it led to an overall decrease in WFA labeling around PV cells (Fig. 3).This indicates that although PNNs limit oxidative stress and protect PV cells, they are also by themselves sensitive to excess amounts of oxidative stress.We then investigated the effects of a cell-autonomous redox dysregulation on PV immunoreactivity and WFA-labeled PNNs.We generated mice whose PV cells were fully incapable of synthesizing GSH by a restricted deletion of the gene coding for the catalytic subunit of glutamate cysteine ligase (GCLC), only in PV cells.PV-Gclc KO mice showed a progressive GCLC deletion in PV-expressing cells, with ∼70% of PV-Cre(+) cells displaying no Gclc mRNA in the cerebral cortex of 2-mo-old animals.These conditional KO mice displayed a much stronger 8-oxo-dG labeling within PV cells compared with PV-Gclc WT mice (Fig. 4 A and B) or Gclm KO mice (Fig. S4).Under such severe cell-autonomous redox dysregulation, significantly fewer PV immunoreactive cells and WFA-labeled PNNs were observed (Fig. 4 C and D).In cortical layers enriched in PV cells, some cells displayed strong 8-oxo-dG labeling, although they were neither PV immunoreactive (Fig. 4A) nor enwrapped by WFA-labeled PNNs.These may represent PV cells that had already lost PV immunoreactivity.However, in this model, it remains unclear whether the loss of WFA-labeled PNNs precedes the loss of PV expression or whether it is the consequence of PV-cell dysfunction or degeneration. Degradation of Mature PNNs Renders PV Cells More Susceptible to Oxidative Stress.To substantiate whether mature PNNs play a protective role, we stripped them off the ACC of young adult (P90) Gclm KO mice and monitored PV-cell susceptibility to oxidative stress, using GBR.The chondroitinase ABC (ChABC) enzyme was locally injected into one ACC, and the contralateral side received a vehicle (sham).ChABC injection efficiently degraded PNNs unilaterally, as verified 2 d postinjection by the absence of WFA labeling in the treated ACC (Fig. S5).After ChABC injection, mice were further treated for 11 consecutive days with either GBR or a vehicle (PBS) and then killed (Fig. 5D).In both PBS-treated (n = 5) and GBR-treated (n = 7) mice, WFA labeling in the ChABC-injected ACC was faint and significantly weaker than in sham ACC (P < 0.001; Fig. 5A).However, only GBR caused a significant decrease in the number of PV immunoreactive cells in the ChABC-injected ACC compared with the contralateral side (Fig. 5B).The 8-oxo-dG labeling after GBR treatment was likewise significantly higher in ChABC-injected than in sham ACC (Fig. 5C).PNN degradation did not, however, affect the number of calbindin-and calretininimmunoreactive cells when subjected to GBR-induced oxidative stress (Fig. S6).This demonstrates that mature PNNs specifically protect PV cells from additional oxidative stress. Finally, we functionally assessed whether PNN degradation rendered local PV-cell networks vulnerable to further oxidative stress.Fast rhythmic oscillations reflecting neuronal synchronization were clearly altered in slices of ChABC-injected ACC from the P90 GBR-treated Gclm KO mice [significant interaction between treatment (PBS vs. GBR) and PNN status (ChABC vs. contralateral sham), multivariate analysis; P = 0.039].In control PBS-treated Gclm KO mice, the power of oscillations (induced by coapplication of carbachol, kainic acid, and quinpirole) tended to be stronger in the ChABC-injected side compared with contralateral sham ACC (Fig. 5E).Instead, in GBR-treated Gclm KO mice, the power of oscillations tended to be weaker in the ChABC-injected side compared with sham ACC (Fig. 5F).Thus, a lack of PNNs favors β/γ oscillatory power, which is then weakened during oxidative stress challenge, consistent with the reduced number of PV immunoreactive cells under the latter condition (Fig. 5B).
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the additional oxidative stress generated by GBR did not affect PV immunoreactivity in P90 Gclm KO mice (Fig. 2B), it led to an overall decrease in WFA labeling around PV cells (Fig. 3).”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > PNNs Are Themselves Sensitive to Excessive Redox Dysregulation. Although the additional oxidative stress generated by GBR did not affect PV immunoreactivity in P90 Gclm KO mice (Fig. 2B), it led to an overall decrease in WFA labeling around PV cells (Fig. 3).This indicates that although PNNs limit oxidative stress and protect PV cells, they are also by themselves sensitive to excess amounts of oxidative stress.We then investigated the effects of a cell-autonomous redox dysregulation on PV immunoreactivity and WFA-labeled PNNs.We generated mice whose PV cells were fully incapable of synthesizing GSH by a restricted deletion of the gene coding for the catalytic subunit of glutamate cysteine ligase (GCLC), only in PV cells.PV-Gclc KO mice showed a progressive GCLC deletion in PV-expressing cells, with ∼70% of PV-Cre(+) cells displaying no Gclc mRNA in the cerebral cortex of 2-mo-old animals.These conditional KO mice displayed a much stronger 8-oxo-dG labeling within PV cells compared with PV-Gclc WT mice (Fig. 4 A and B) or Gclm KO mice (Fig. S4).Under such severe cell-autonomous redox dysregulation, significantly fewer PV immunoreactive cells and WFA-labeled PNNs were observed (Fig. 4 C and D).In cortical layers enriched in PV cells, some cells displayed strong 8-oxo-dG labeling, although they were neither PV immunoreactive (Fig. 4A) nor enwrapped by WFA-labeled PNNs.These may represent PV cells that had already lost PV immunoreactivity.However, in this model, it remains unclear whether the loss of WFA-labeled PNNs precedes the loss of PV expression or whether it is the consequence of PV-cell dysfunction or degeneration. Degradation of Mature PNNs Renders PV Cells More Susceptible to Oxidative Stress.To substantiate whether mature PNNs play a protective role, we stripped them off the ACC of young adult (P90) Gclm KO mice and monitored PV-cell susceptibility to oxidative stress, using GBR.The chondroitinase ABC (ChABC) enzyme was locally injected into one ACC, and the contralateral side received a vehicle (sham).ChABC injection efficiently degraded PNNs unilaterally, as verified 2 d postinjection by the absence of WFA labeling in the treated ACC (Fig. S5).After ChABC injection, mice were further treated for 11 consecutive days with either GBR or a vehicle (PBS) and then killed (Fig. 5D).In both PBS-treated (n = 5) and GBR-treated (n = 7) mice, WFA labeling in the ChABC-injected ACC was faint and significantly weaker than in sham ACC (P < 0.001; Fig. 5A).However, only GBR caused a significant decrease in the number of PV immunoreactive cells in the ChABC-injected ACC compared with the contralateral side (Fig. 5B).The 8-oxo-dG labeling after GBR treatment was likewise significantly higher in ChABC-injected than in sham ACC (Fig. 5C).PNN degradation did not, however, affect the number of calbindin-and calretininimmunoreactive cells when subjected to GBR-induced oxidative stress (Fig. S6).This demonstrates that mature PNNs specifically protect PV cells from additional oxidative stress. Finally, we functionally assessed whether PNN degradation rendered local PV-cell networks vulnerable to further oxidative stress.Fast rhythmic oscillations reflecting neuronal synchronization were clearly altered in slices of ChABC-injected ACC from the P90 GBR-treated Gclm KO mice [significant interaction between treatment (PBS vs. GBR) and PNN status (ChABC vs. contralateral sham), multivariate analysis; P = 0.039].In control PBS-treated Gclm KO mice, the power of oscillations (induced by coapplication of carbachol, kainic acid, and quinpirole) tended to be stronger in the ChABC-injected side compared with contralateral sham ACC (Fig. 5E).Instead, in GBR-treated Gclm KO mice, the power of oscillations tended to be weaker in the ChABC-injected side compared with sham ACC (Fig. 5F).Thus, a lack of PNNs favors β/γ oscillatory power, which is then weakened during oxidative stress challenge, consistent with the reduced number of PV immunoreactive cells under the latter condition (Fig. 5B).
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The number of PV cells with WFA-labeled PNNs [54.8 ± 7.5 (KO) vs. 52.8± 9.2 (WT)] and the overall intensity of WFA labeling [arbitrary unit: 2.9 ± 0.2 (KO) vs. 3.0 ± 0.9 (WT)] were not significantly different between genotypes.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Results
plainn = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PV-Gclc KO mice showed a progressive GCLC deletion in PV-expressing cells, with ∼70% of PV-Cre(+) cells displaying no Gclc mRNA in the cerebral cortex of 2-mo-old animals.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > PNNs Are Themselves Sensitive to Excessive Redox Dysregulation. Although the additional oxidative stress generated by GBR did not affect PV immunoreactivity in P90 Gclm KO mice (Fig. 2B), it led to an overall decrease in WFA labeling around PV cells (Fig. 3).This indicates that although PNNs limit oxidative stress and protect PV cells, they are also by themselves sensitive to excess amounts of oxidative stress.We then investigated the effects of a cell-autonomous redox dysregulation on PV immunoreactivity and WFA-labeled PNNs.We generated mice whose PV cells were fully incapable of synthesizing GSH by a restricted deletion of the gene coding for the catalytic subunit of glutamate cysteine ligase (GCLC), only in PV cells.PV-Gclc KO mice showed a progressive GCLC deletion in PV-expressing cells, with ∼70% of PV-Cre(+) cells displaying no Gclc mRNA in the cerebral cortex of 2-mo-old animals.These conditional KO mice displayed a much stronger 8-oxo-dG labeling within PV cells compared with PV-Gclc WT mice (Fig. 4 A and B) or Gclm KO mice (Fig. S4).Under such severe cell-autonomous redox dysregulation, significantly fewer PV immunoreactive cells and WFA-labeled PNNs were observed (Fig. 4 C and D).In cortical layers enriched in PV cells, some cells displayed strong 8-oxo-dG labeling, although they were neither PV immunoreactive (Fig. 4A) nor enwrapped by WFA-labeled PNNs.These may represent PV cells that had already lost PV immunoreactivity.However, in this model, it remains unclear whether the loss of WFA-labeled PNNs precedes the loss of PV expression or whether it is the consequence of PV-cell dysfunction or degeneration. Degradation of Mature PNNs Renders PV Cells More Susceptible to Oxidative Stress.To substantiate whether mature PNNs play a protective role, we stripped them off the ACC of young adult (P90) Gclm KO mice and monitored PV-cell susceptibility to oxidative stress, using GBR.The chondroitinase ABC (ChABC) enzyme was locally injected into one ACC, and the contralateral side received a vehicle (sham).ChABC injection efficiently degraded PNNs unilaterally, as verified 2 d postinjection by the absence of WFA labeling in the treated ACC (Fig. S5).After ChABC injection, mice were further treated for 11 consecutive days with either GBR or a vehicle (PBS) and then killed (Fig. 5D).In both PBS-treated (n = 5) and GBR-treated (n = 7) mice, WFA labeling in the ChABC-injected ACC was faint and significantly weaker than in sham ACC (P < 0.001; Fig. 5A).However, only GBR caused a significant decrease in the number of PV immunoreactive cells in the ChABC-injected ACC compared with the contralateral side (Fig. 5B).The 8-oxo-dG labeling after GBR treatment was likewise significantly higher in ChABC-injected than in sham ACC (Fig. 5C).PNN degradation did not, however, affect the number of calbindin-and calretininimmunoreactive cells when subjected to GBR-induced oxidative stress (Fig. S6).This demonstrates that mature PNNs specifically protect PV cells from additional oxidative stress. Finally, we functionally assessed whether PNN degradation rendered local PV-cell networks vulnerable to further oxidative stress.Fast rhythmic oscillations reflecting neuronal synchronization were clearly altered in slices of ChABC-injected ACC from the P90 GBR-treated Gclm KO mice [significant interaction between treatment (PBS vs. GBR) and PNN status (ChABC vs. contralateral sham), multivariate analysis; P = 0.039].In control PBS-treated Gclm KO mice, the power of oscillations (induced by coapplication of carbachol, kainic acid, and quinpirole) tended to be stronger in the ChABC-injected side compared with contralateral sham ACC (Fig. 5E).Instead, in GBR-treated Gclm KO mice, the power of oscillations tended to be weaker in the ChABC-injected side compared with sham ACC (Fig. 5F).Thus, a lack of PNNs favors β/γ oscillatory power, which is then weakened during oxidative stress challenge, consistent with the reduced number of PV immunoreactive cells under the latter condition (Fig. 5B).
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GBR induced a significant increase of 8-oxo-dG signal in the entire ACC of Gclm KO mice at both ages (P20 and P90), but the labeling was significantly higher at P20 (Fig. 2C).”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“(D) PV cells (red or arrowheads) surrounded by dense WFA-labeled PNNs (light blue, pseudocolor modified for improved visibility) display low levels of 8-oxo-dG signal (green), and vice versa.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Immunostaining, Confocal Microscopy, and Image Analysis.
plaincorrelationaln = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Note that the peak frequencies of both β and γ oscillations do not differ significantly across genotypes”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Immunostaining, Confocal Microscopy, and Image Analysis.
plainn = 11- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“(D) Quantification indicates significant decrease in number of PV immunoreactive cells (Left) and PNNs (Right) in PV-Gclc KO mice (n = 5 per group).”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Immunostaining, Confocal Microscopy, and Image Analysis.
hedgedcorrelationaln = 5- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“(B) GBR (n = 7), but not PBS (n = 5), induces a significant decrease in PV immunoreactive cells in ChABC-injected ACC.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Immunostaining, Confocal Microscopy, and Image Analysis.
plaindirectn = 7- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, accumulated oxidative stress resulting from a very long chronic redox dysregulation (as in P180 mice but not P90 mice) impairs many PV cells and their associated local neuronal synchrony while sparing those PV cells bearing well-formed PNNs.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).”
What the sources say
- Not checked — no full text of the sourcecites [16] 16. Spencer KM, Niznikiewicz MA, Shenton ME, McCarley RW (2008) Sensory-evoked gamma oscillations in chronic schizophrenia. Biol Psychiatry 63(8):744-747. source
- Not checked — no full text of the sourcecites [17] 17. Uhlhaas PJ, Singer W (2011) The development of neural synchrony and large-scale cortical networks during adolescence: Relevance for the pathophysiology of schizo- phrenia and neurodevelopmental hypothesis. Schizophr Bull 37(3):514-523. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these data suggest that fully mature WFA-labeled PNNs (as seen in P90 Gclm KO mice) are able to limit the GBR-induced increase in oxidative stress throughout the ACC, and therefore prevent PV-cell impairment at this age.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Results
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).”
What the sources say
- Not checked — no full text of the sourcecites [34] 34. Kwok JC, Dick G, Wang D, Fawcett JW (2011) Extracellular matrix and perineuronal nets in CNS repair. Dev Neurobiol 71(11):1073-1089. source
- Not checked — no full text of the sourcecites [35] 35. Sugiyama S, Prochiantz A, Hensch TK (2009) From brain formation to plasticity: In- sights on Otx2 homeoprotein. Dev Growth Differ 51(3):369-377. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This indicates that although PNNs limit oxidative stress and protect PV cells, they are also by themselves sensitive to excess amounts of oxidative stress.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > PNNs Are Themselves Sensitive to Excessive Redox Dysregulation. Although the additional oxidative stress generated by GBR did not affect PV immunoreactivity in P90 Gclm KO mice (Fig. 2B), it led to an overall decrease in WFA labeling around PV cells (Fig. 3).This indicates that although PNNs limit oxidative stress and protect PV cells, they are also by themselves sensitive to excess amounts of oxidative stress.We then investigated the effects of a cell-autonomous redox dysregulation on PV immunoreactivity and WFA-labeled PNNs.We generated mice whose PV cells were fully incapable of synthesizing GSH by a restricted deletion of the gene coding for the catalytic subunit of glutamate cysteine ligase (GCLC), only in PV cells.PV-Gclc KO mice showed a progressive GCLC deletion in PV-expressing cells, with ∼70% of PV-Cre(+) cells displaying no Gclc mRNA in the cerebral cortex of 2-mo-old animals.These conditional KO mice displayed a much stronger 8-oxo-dG labeling within PV cells compared with PV-Gclc WT mice (Fig. 4 A and B) or Gclm KO mice (Fig. S4).Under such severe cell-autonomous redox dysregulation, significantly fewer PV immunoreactive cells and WFA-labeled PNNs were observed (Fig. 4 C and D).In cortical layers enriched in PV cells, some cells displayed strong 8-oxo-dG labeling, although they were neither PV immunoreactive (Fig. 4A) nor enwrapped by WFA-labeled PNNs.These may represent PV cells that had already lost PV immunoreactivity.However, in this model, it remains unclear whether the loss of WFA-labeled PNNs precedes the loss of PV expression or whether it is the consequence of PV-cell dysfunction or degeneration. Degradation of Mature PNNs Renders PV Cells More Susceptible to Oxidative Stress.To substantiate whether mature PNNs play a protective role, we stripped them off the ACC of young adult (P90) Gclm KO mice and monitored PV-cell susceptibility to oxidative stress, using GBR.The chondroitinase ABC (ChABC) enzyme was locally injected into one ACC, and the contralateral side received a vehicle (sham).ChABC injection efficiently degraded PNNs unilaterally, as verified 2 d postinjection by the absence of WFA labeling in the treated ACC (Fig. S5).After ChABC injection, mice were further treated for 11 consecutive days with either GBR or a vehicle (PBS) and then killed (Fig. 5D).In both PBS-treated (n = 5) and GBR-treated (n = 7) mice, WFA labeling in the ChABC-injected ACC was faint and significantly weaker than in sham ACC (P < 0.001; Fig. 5A).However, only GBR caused a significant decrease in the number of PV immunoreactive cells in the ChABC-injected ACC compared with the contralateral side (Fig. 5B).The 8-oxo-dG labeling after GBR treatment was likewise significantly higher in ChABC-injected than in sham ACC (Fig. 5C).PNN degradation did not, however, affect the number of calbindin-and calretininimmunoreactive cells when subjected to GBR-induced oxidative stress (Fig. S6).This demonstrates that mature PNNs specifically protect PV cells from additional oxidative stress. Finally, we functionally assessed whether PNN degradation rendered local PV-cell networks vulnerable to further oxidative stress.Fast rhythmic oscillations reflecting neuronal synchronization were clearly altered in slices of ChABC-injected ACC from the P90 GBR-treated Gclm KO mice [significant interaction between treatment (PBS vs. GBR) and PNN status (ChABC vs. contralateral sham), multivariate analysis; P = 0.039].In control PBS-treated Gclm KO mice, the power of oscillations (induced by coapplication of carbachol, kainic acid, and quinpirole) tended to be stronger in the ChABC-injected side compared with contralateral sham ACC (Fig. 5E).Instead, in GBR-treated Gclm KO mice, the power of oscillations tended to be weaker in the ChABC-injected side compared with sham ACC (Fig. 5F).Thus, a lack of PNNs favors β/γ oscillatory power, which is then weakened during oxidative stress challenge, consistent with the reduced number of PV immunoreactive cells under the latter condition (Fig. 5B).
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).”
What the sources say
- Not checked — no full text of the sourcecites [4] 4. Whittington MA, Cunningham MO, LeBeau FE, Racca C, Traub RD (2011) Multiple origins of the cortical γ rhythm. Dev Neurobiol 71(1):92-106. source
- Not checked — no full text of the sourcecites [5] 5. Cabungcal JH, Steullet P, Kraftsik R, Cuenod M, Do KQ (2013) Early-life insults impair parvalbumin interneurons via oxidative stress: Reversal by N-acetylcysteine. Biol Psy- chiatry 73(6):574-582. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).”
What the sources say
- Not matchedcites [20] 20. Do KQ, et al. (2000) Schizophrenia: Glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci 12(10):3721-3728.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“GBR increases extracellular dopamine, which in turn generates reactive oxygen species (ROS) (39,40) in regions richly innervated by dopaminergic terminals, such as the ACC.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Results
What the sources say
- Not checked — no full text of the sourcecites [39] 39. Steullet P, et al. (2010) Redox dysregulation affects the ventral but not dorsal hip- pocampus: Impairment of parvalbumin neurons, gamma oscillations, and related behaviors. J Neurosci 30(7):2547-2558. source
- Not checked — no full text of the sourcecites [40] 40. Härtig W, Brauer K, Bigl V, Brückner G (1994) Chondroitin sulfate proteoglycan- immunoreactivity of lectin-labeled perineuronal nets around parvalbumin-containing neurons. Brain Res 635(1-2):307-311. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These may represent PV cells that had already lost PV immunoreactivity.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > PNNs Are Themselves Sensitive to Excessive Redox Dysregulation. Although the additional oxidative stress generated by GBR did not affect PV immunoreactivity in P90 Gclm KO mice (Fig. 2B), it led to an overall decrease in WFA labeling around PV cells (Fig. 3).This indicates that although PNNs limit oxidative stress and protect PV cells, they are also by themselves sensitive to excess amounts of oxidative stress.We then investigated the effects of a cell-autonomous redox dysregulation on PV immunoreactivity and WFA-labeled PNNs.We generated mice whose PV cells were fully incapable of synthesizing GSH by a restricted deletion of the gene coding for the catalytic subunit of glutamate cysteine ligase (GCLC), only in PV cells.PV-Gclc KO mice showed a progressive GCLC deletion in PV-expressing cells, with ∼70% of PV-Cre(+) cells displaying no Gclc mRNA in the cerebral cortex of 2-mo-old animals.These conditional KO mice displayed a much stronger 8-oxo-dG labeling within PV cells compared with PV-Gclc WT mice (Fig. 4 A and B) or Gclm KO mice (Fig. S4).Under such severe cell-autonomous redox dysregulation, significantly fewer PV immunoreactive cells and WFA-labeled PNNs were observed (Fig. 4 C and D).In cortical layers enriched in PV cells, some cells displayed strong 8-oxo-dG labeling, although they were neither PV immunoreactive (Fig. 4A) nor enwrapped by WFA-labeled PNNs.These may represent PV cells that had already lost PV immunoreactivity.However, in this model, it remains unclear whether the loss of WFA-labeled PNNs precedes the loss of PV expression or whether it is the consequence of PV-cell dysfunction or degeneration. Degradation of Mature PNNs Renders PV Cells More Susceptible to Oxidative Stress.To substantiate whether mature PNNs play a protective role, we stripped them off the ACC of young adult (P90) Gclm KO mice and monitored PV-cell susceptibility to oxidative stress, using GBR.The chondroitinase ABC (ChABC) enzyme was locally injected into one ACC, and the contralateral side received a vehicle (sham).ChABC injection efficiently degraded PNNs unilaterally, as verified 2 d postinjection by the absence of WFA labeling in the treated ACC (Fig. S5).After ChABC injection, mice were further treated for 11 consecutive days with either GBR or a vehicle (PBS) and then killed (Fig. 5D).In both PBS-treated (n = 5) and GBR-treated (n = 7) mice, WFA labeling in the ChABC-injected ACC was faint and significantly weaker than in sham ACC (P < 0.001; Fig. 5A).However, only GBR caused a significant decrease in the number of PV immunoreactive cells in the ChABC-injected ACC compared with the contralateral side (Fig. 5B).The 8-oxo-dG labeling after GBR treatment was likewise significantly higher in ChABC-injected than in sham ACC (Fig. 5C).PNN degradation did not, however, affect the number of calbindin-and calretininimmunoreactive cells when subjected to GBR-induced oxidative stress (Fig. S6).This demonstrates that mature PNNs specifically protect PV cells from additional oxidative stress. Finally, we functionally assessed whether PNN degradation rendered local PV-cell networks vulnerable to further oxidative stress.Fast rhythmic oscillations reflecting neuronal synchronization were clearly altered in slices of ChABC-injected ACC from the P90 GBR-treated Gclm KO mice [significant interaction between treatment (PBS vs. GBR) and PNN status (ChABC vs. contralateral sham), multivariate analysis; P = 0.039].In control PBS-treated Gclm KO mice, the power of oscillations (induced by coapplication of carbachol, kainic acid, and quinpirole) tended to be stronger in the ChABC-injected side compared with contralateral sham ACC (Fig. 5E).Instead, in GBR-treated Gclm KO mice, the power of oscillations tended to be weaker in the ChABC-injected side compared with sham ACC (Fig. 5F).Thus, a lack of PNNs favors β/γ oscillatory power, which is then weakened during oxidative stress challenge, consistent with the reduced number of PV immunoreactive cells under the latter condition (Fig. 5B).
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).”
What the sources say
- Not checked — no full text of the sourcecites [31] 31. Kulak A, et al. (2013) Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: Insights from animal models. Antioxid Redox Signal 18(12): 1428-1443. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).”
What the sources say
- Not matchedcites (18)(19)(20)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).”
What the sources say
- Not matchedcites (6)(7)(8)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).”
What the sources say
- Not matchedcites (reviewed in refs.32 and 33)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, intact PNNs could serve as a protective shield to neutralize ROS either directly and/or via activation of intracellular pathways to boost the cellular antioxidant capacity.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Only recordings from slices displaying little or no WFA labeling in the ChABC-injected ACC compared with the contralateral sham ACC were analyzed.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Immunostaining, Confocal Microscopy, and Image Analysis.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“which binds PNNs without causing any inflammatory processes (56)”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Surgery and Chondroitinase ABC Treatment.
What the sources say
- Not checked — no full text of the sourcecites [56] 56. Gandal MJ, Nesbitt AM, McCurdy RM, Alter MD (2012) Measuring the maturity of the fast-spiking interneuron transcriptional program in autism, schizophrenia, and bi- polar disorder. PLoS ONE 7(8):e41215. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This, in turn, decreases lipid peroxidation, DNA damage, and protein oxidation.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“ChABC degrades chondroitin sulfate proteoglycans, which are a major component of the PNNs (32).”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Surgery and Chondroitinase ABC Treatment.
What the sources say
- Not checked — no full text of the sourcecites [32] 32. Giamanco KA, Morawski M, Matthews RT (2010) Perineuronal net formation and structure in aggrecan knockout mice. Neuroscience 170(4):1314-1327. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data provide a unique function and therapeutic insight presented by this specialized extracellular matrix structure in psychiatric disorders.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This verification was done blindly before performing the electrophysiological analysis.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Immunostaining, Confocal Microscopy, and Image Analysis.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Components of the PNNs, such as hyaluronan and chondroitin sulfate, have antioxidant properties (44,45) and can reduce the generation of hydroxyl radical (OH_) via their capacity to chelate transition metals and limit the initiation of Harber-Weiss and Fenton's reactions.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Discussion
What the sources say
- Not checked — no full text of the sourcecites [44] 44. Lataster J, et al. (2011) Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: A positron emission tomography study using [¹⁸F]fallypride. Neuroimage 58(4):1081-1089. source
- Not checked — no full text of the sourcecites [45] 45. Morawski M, et al. (2004) The binding of iron to perineuronal nets: A combined nuclear microscopy and Mössbauer study. Hyperfine Interact 159:285-291. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, a lack of PNNs favors β/γ oscillatory power, which is then weakened during oxidative stress challenge, consistent with the reduced number of PV immunoreactive cells under the latter condition (Fig. 5B).”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > PNNs Are Themselves Sensitive to Excessive Redox Dysregulation. Although the additional oxidative stress generated by GBR did not affect PV immunoreactivity in P90 Gclm KO mice (Fig. 2B), it led to an overall decrease in WFA labeling around PV cells (Fig. 3).This indicates that although PNNs limit oxidative stress and protect PV cells, they are also by themselves sensitive to excess amounts of oxidative stress.We then investigated the effects of a cell-autonomous redox dysregulation on PV immunoreactivity and WFA-labeled PNNs.We generated mice whose PV cells were fully incapable of synthesizing GSH by a restricted deletion of the gene coding for the catalytic subunit of glutamate cysteine ligase (GCLC), only in PV cells.PV-Gclc KO mice showed a progressive GCLC deletion in PV-expressing cells, with ∼70% of PV-Cre(+) cells displaying no Gclc mRNA in the cerebral cortex of 2-mo-old animals.These conditional KO mice displayed a much stronger 8-oxo-dG labeling within PV cells compared with PV-Gclc WT mice (Fig. 4 A and B) or Gclm KO mice (Fig. S4).Under such severe cell-autonomous redox dysregulation, significantly fewer PV immunoreactive cells and WFA-labeled PNNs were observed (Fig. 4 C and D).In cortical layers enriched in PV cells, some cells displayed strong 8-oxo-dG labeling, although they were neither PV immunoreactive (Fig. 4A) nor enwrapped by WFA-labeled PNNs.These may represent PV cells that had already lost PV immunoreactivity.However, in this model, it remains unclear whether the loss of WFA-labeled PNNs precedes the loss of PV expression or whether it is the consequence of PV-cell dysfunction or degeneration. Degradation of Mature PNNs Renders PV Cells More Susceptible to Oxidative Stress.To substantiate whether mature PNNs play a protective role, we stripped them off the ACC of young adult (P90) Gclm KO mice and monitored PV-cell susceptibility to oxidative stress, using GBR.The chondroitinase ABC (ChABC) enzyme was locally injected into one ACC, and the contralateral side received a vehicle (sham).ChABC injection efficiently degraded PNNs unilaterally, as verified 2 d postinjection by the absence of WFA labeling in the treated ACC (Fig. S5).After ChABC injection, mice were further treated for 11 consecutive days with either GBR or a vehicle (PBS) and then killed (Fig. 5D).In both PBS-treated (n = 5) and GBR-treated (n = 7) mice, WFA labeling in the ChABC-injected ACC was faint and significantly weaker than in sham ACC (P < 0.001; Fig. 5A).However, only GBR caused a significant decrease in the number of PV immunoreactive cells in the ChABC-injected ACC compared with the contralateral side (Fig. 5B).The 8-oxo-dG labeling after GBR treatment was likewise significantly higher in ChABC-injected than in sham ACC (Fig. 5C).PNN degradation did not, however, affect the number of calbindin-and calretininimmunoreactive cells when subjected to GBR-induced oxidative stress (Fig. S6).This demonstrates that mature PNNs specifically protect PV cells from additional oxidative stress. Finally, we functionally assessed whether PNN degradation rendered local PV-cell networks vulnerable to further oxidative stress.Fast rhythmic oscillations reflecting neuronal synchronization were clearly altered in slices of ChABC-injected ACC from the P90 GBR-treated Gclm KO mice [significant interaction between treatment (PBS vs. GBR) and PNN status (ChABC vs. contralateral sham), multivariate analysis; P = 0.039].In control PBS-treated Gclm KO mice, the power of oscillations (induced by coapplication of carbachol, kainic acid, and quinpirole) tended to be stronger in the ChABC-injected side compared with contralateral sham ACC (Fig. 5E).Instead, in GBR-treated Gclm KO mice, the power of oscillations tended to be weaker in the ChABC-injected side compared with sham ACC (Fig. 5F).Thus, a lack of PNNs favors β/γ oscillatory power, which is then weakened during oxidative stress challenge, consistent with the reduced number of PV immunoreactive cells under the latter condition (Fig. 5B).
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Some cells without PV but with strong 8-oxo-dG labeling may have lost their PV immunoreactivity.”
§ Perineuronal nets protect fast-spiking interneurons against oxidative stress A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks.The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress.Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress.These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults.We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display.Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress.In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets.Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress.The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets.Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.critical period | extracellular matrix | glutamate cysteine ligase | glutathione | neuronal synchronization F ast-spiking interneurons expressing parvalbumin (PV) con- stitute a subpopulation of GABA cells that control the output of principal neurons and are necessary for fast rhythmic neuronal synchrony, facilitating information processing during cognitive tasks (1,2).To coordinate the activity of neuronal assemblies, PV cells are interconnected by both chemical and electrical synapses, have the capacity to fire at high frequency without adaptation, and selectively position inhibitory synaptic terminals onto the cell body and axon initial segment of their target neurons.Fast-spiking properties consequently impose high metabolic demand and increased mitochondrial density, which renders PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress (3).For instance, ketamine induces superoxide overproduction that strongly impairs PV cells (i.e., loss of normal phenotype including PV immunoreactivity but without cell death) (4,5).Moreover, severe environmental stressors produce oxidative stress in the brain and impair PV cells (6)(7)(8).Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).Abnormal neuronal synchrony in γ-frequency (30-80 Hz) and β-frequency (13-28 Hz) bands during sensory and cognitive processing tasks (12)(13)(14)(15) further indicates a PV cell network dysfunction in schizophrenia.Parallel evidence of oxidative stress and altered antioxidant response is also found both in schizophrenia and in bipolar disorder (16,17).Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20).Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23-27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29). Here, we explore whether these metabolically intense interneurons have evolved unique protective mechanisms to limit their intrinsic vulnerability.When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31).The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.32 and 33).It has also been suggested that PNNs may protect neurons against iron sequestration and oxidative stress (34,35).Therefore, we examined the relationship between the PNNs around PV cells and oxidative stress in mice that suffer from a genetic redox dysregulation and that are consequently more susceptible to oxidative stress.These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37) and represent a valid animal model, as low brain GSH levels (18,19) and genetic association with GCLM have been reported in schizophrenia (22).We assessed both the cumulative effect of chronic redox dysregulation and the effect of additional oxidative challenges applied at different ages.The anterior cingulate cortex (ACC) was chosen as a prefrontal area known to be affected and to display redox dysregulation in schizophrenia (20).In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress. > Immunostaining, Confocal Microscopy, and Image Analysis.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
PNNs control the accumulation of Otx2 within PV cells.
“Importantly, PNNs control the accumulation of a noncell autonomous homeoprotein, orthodenticle homeobox 2 (Otx2), within PV cells.”
The paper relies on this without support.
Severe life event stresses, through activation of the hypothalamic-pituitary-adrenal axis, induce release of dopamine, whose catabolism generates ROS.
“Severe life event stresses, through activation of the hypothalamic-pituitary-adrenal axis, induce a vital release of dopamine, the catabolism of which is known to generate ROS.”
The paper relies on this without support.
Traumatic experiences during childhood enhance risk for psychosis.
“Traumatic experiences during childhood thus enhance the risk for psychosis.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“PNNs are believed to protect neurons from oxidative stress (Morawski et al., 2004;Cabungcal et al., 2013), perhaps by limiting GABAergic interneuron excitability.”
From Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity (2016) · cites this paper as Cabungcal et al., 2013
The cited source says what the claim attributes to it.
In the citing paper
“PNNs protect against oxidative stress (Morawski et al., 2004;Cabungcal et al., 2013)”
From Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity (2016) · cites this paper as Cabungcal et al., 2013
In the citing paper
“The high metabolic requirements of the fast-spiking PV-interneuron (23) may readily generate reactive oxygen species when their antioxidant systems are impaired, leading to the breakdown of PNNs themselves (Figure 2C,D) (53).”
From Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons (2015) · cites this paper as [53]
In the citing paper
“Our recent study revealed a protective function of these PNNs as a redox sensor (53).”
From Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons (2015) · cites this paper as [53]
In the citing paper
“which may be protected by PNNs (Cabungcal et al., 2013).”
From Choroid-Plexus-Derived Otx2 Homeoprotein Constrains Adult Cortical Plasticity (2013) · cites this paper as Cabungcal et al., 2013
In the citing paper
“we previously observed that both in normal-aged brain and AD neurons ensheathed by a PN are less frequently affected by lipofuscin accumulation than neurons without a net.”
From Aggrecan, link protein and tenascin-R are essential components of the perineuronal net to protect neurons against iron-induced oxidative stress (2014) · cites this paper as [31]
In the citing paper
“As lipofuscin is an intralysosomal pigment composed of cross-linked proteins and lipids generated by iron-catalysed oxidative processes, this finding suggests a neuroprotective function of PNs against neurodegeneration induced by oxidative stress.22, 23, 29, 30, 31”
From Aggrecan, link protein and tenascin-R are essential components of the perineuronal net to protect neurons against iron-induced oxidative stress (2014) · cites this paper as [31]
In the citing paper
“Models of oxidative stress relevant to this disorder show reductions of PNNs,8”
From Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala (2015) · cites this paper as [8]
In the citing paper
“PNNs may regulate PV cell functions (Hensch, 2005; Cabungcal et al., 2013; Bernard and Prochiantz, 2016), as PNN reorganization is shown to result in abnormal CNS development and altered neural excitability (Pizzorusso et al., 2002; Dityatev et al., 2007; Liu et al., 2013; Balmer, 2016; Lensjø et al., 2017).”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Cabungcal et al., 2013
In the citing paper
“Recent studies show that PNNs may protect PV cells from oxidative stress (Cabungcal et al., 2013; Morishita et al., 2015), and thus serve as a ‘safety net’ to support the rapid firing properties of PV cells.”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Cabungcal et al., 2013
In the citing paper
“As PNNs regulate PV cell activity (Balmer, 2016; Lensjø et al., 2017) and protect PV cells from oxidative stress (Cabungcal et al., 2013), PNNs can be potentially targeted to control seizures.”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Cabungcal et al., 2013
In the citing paper
“High MMP-9 levels may result in reduced PNN formation around PV interneurons affecting their activity (Cabungcal et al., 2013) and leading to impaired inhibition (Selby et al., 2007; Gibson et al., 2008), and enhanced excitability in Fmr1 KO auditory cortex.”
From Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome (2016) · cites this paper as Cabungcal et al., 2013
In the citing paper
“On the other hand it was observed in mice that PNN protects FS-PV interneurons against oxidative stress.14, 15”
From Cortical fast-spiking parvalbumin interneurons enwrapped in the perineuronal net express the metallopeptidases Adamts8, Adamts15 and Neprilysin (2015) · cites this paper as [14]
In the citing paper
“Emerging evidence shows that PNNs may play a key role in protecting neurons from oxidative stress, such as it may be caused by a decrease of glutathione, a key brain antioxidant found to be decreased in SZ (Cabungcal et al., 2013; Gawryluk et al., 2011; Suttkus et al., 2014).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Cabungcal et al., 2013
In the citing paper
“As proposed by Do and coworkers, the protection afforded to GABAergic neurons by PNNs might reflect a balance between the oxidative burden on these ECM structures and the capacity of the system to maintain them (Cabungcal et al., 2013).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Cabungcal et al., 2013
In the citing paper
“However, PNNs may in turn be vulnerable to oxidative stress, as shown in mice with a genetic redox dysregulation (Cabungcal et al., 2013).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Cabungcal et al., 2013
In the citing paper
“PNNs have been implicated in ion homeostasis around highly active neurons (Bruckner et al., 1993; Bruckner et al., 1996a; Bruckner et al., 1996b; Hartig et al., 1999; Hartig et al., 2001; Hobohm et al., 1998) and neuroprotection”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Cabungcal et al., 2013
In the citing paper
“enzymatic degradation of PNNs with ChABC rendered mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Cabungcal et al., 2013
In the citing paper
“PNN deficit within these mice preferentially affected parvalbumin-containing inhibitory interneurons with a concomitant reduction in neural oscillations in the beta and gamma frequency bands (Cabungcal et al., 2013)”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Cabungcal et al., 2013
In the citing paper
“the frequency of gamma band oscillations may actually be increased in mice with a mild PNN deficit (ChABC treatment alone) while the frequency of gamma band oscillations is decreased (compared to controls) once more oxidative stress is placed on the system”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Cabungcal et al., 2013
In the citing paper
“animals with well formed PNNs (viz. high levels of WFA-labeling) were protected against chronic redox dysregulation”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Cabungcal et al., 2013
In the citing paper
“parvalbumin-containing cells in juvenile mice showed higher susceptibility to oxidative stress compared with adult mice (Cabungcal et al., 2013)”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Cabungcal et al., 2013
In the citing paper
“A recent study demonstrated the importance of PNN integrity in reducing the pathophysiologcal sequalae of oxidative stress (Cabungcal et al., 2013)”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Cabungcal et al., 2013
In the citing paper
“Together these findings highlight the possible role of PNNs in protecting the fast-spiking parvalbumin cells against oxidative stress, which in turn prevents the electrophysiological deficits associated with schizophrenia.”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Cabungcal et al., 2013
In the citing paper
“Since perineuronal nets protect these interneurons from oxidative stress and other injuries [161]”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [161]
In the citing paper
“Surprisingly, it can be observed that both D-amino acid oxidase activator and brain derived neurotrophic factor are involved in several oxidative stress pathways [14, 225], but a direct correlation between these two and oxidative stress in BD has not been yet showed.”
From Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches (2016) · cites this paper as [225]
Citations
Cites
Parvalbumin neurons and gamma rhythms enhance cortical circuit performance
Sohal, V. S., Zhang, F., Yizhar, O., & Deisseroth, K. (2009) · Nature · doi:10.1038/nature07991 · Cited by 2,606
Critical period plasticity in local cortical circuits
Hensch, T. K. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1787 · Cited by 2,323
Self-citationReactivation of Ocular Dominance Plasticity in the Adult Visual Cortex
Pizzorusso, T., Medini, P., Berardi, N., Chierzi, S., Fawcett, J. W., & Maffei, L. (2002) · Science · doi:10.1126/science.1072699 · Cited by 1,679
A Developmental Switch in the Response of DRG Neurons to ETS Transcription Factor Signaling
Hippenmeyer, S., Pecho‐Vrieseling, E., Sigrist, M., Portmann, T., Laengle, C., Ladle, D. R., & Arber, S. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030159 · Cited by 1,111
Gawryluk, J. W., Wang, J.-F., Andreazza, A. C., Shao, L., & Young, L. T. (2011) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145710000805 · Cited by 594
Impairments in frontal cortical γ synchrony and cognitive control in schizophrenia
CHO, R. Y., Konecky, R. O., & Carter, C. S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609440103 · Cited by 586
Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase
Behrens, M. M., Ali, S. S., Dao, D. N., Lucero, J., Shekhtman, G., Quick, K. L., & Dugan, L. L. (2007) · Science · doi:10.1126/science.1148045 · Cited by 585
Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo
Do, K. Q., Trabesinger, A. H., Kirsten‐Krüger, M., Lauer, C. J., Dydak, U., Hell, D., Holsboer, F., Boesiger, P., & Cuénod, M. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00229.x · Cited by 540
Self-citationOxidative stress markers in bipolar disorder: A meta-analysis
Andreazza, A. C., Kauer-Sant'Anna, M., Frey, B. N., Bond, D. J., Kapczinski, F., Young, L. T., & Yatham, L. N. (2008) · Journal of Affective Disorders · doi:10.1016/j.jad.2008.04.013 · Cited by 526
Invited Review Free radicals and the pathobiology of brain dopamine systems
Cadet, J. L., & Brannock, C. (1998) · Neurochemistry International · doi:10.1016/s0197-0186(97)00031-4 · Cited by 499
Cited by
Sorted by citations
Items 201–300 of 533
Burket, J. A., & Deutsch, S. I. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.11.017 · Cited by 34
Regulation of the E/I-balance by the neural matrisome
Mueller-Buehl, C., Wegrzyn, D., Bauch, J., & Faissner, A. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1102334 · Cited by 35
Chodankar, A., Sadanandappa, M. K., VijayRaghavan, K., & Ramaswami, M. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2192-19.2020 · Cited by 39
Beebe, N. L., Mellott, J. G., & Schofield, B. R. (2018) · eNeuro · doi:10.1523/eneuro.0406-18.2018 · Cited by 30
Tendilla‐Beltrán, H., Sanchez-Islas, N. D. C., Marina-Ramos, M., Leza, J. C., & Flores, G. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101967 · Cited by 36
Radtke‐Schuller, S., Seeler, S., & Grothe, B. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00004 · Cited by 32
Datta, D., Enwright, J. F., Arion, D., Paspalas, C. D., Morozov, Y. M., Lewis, D. A., & Arnsten, A. F. T. (2020) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2020.578483 · Cited by 31
Saito, M., Smiley, J. F., Hui, M., Masiello, K., Betz, J., Ilina, M., Saito, M., & Wilson, D. A. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy034 · Cited by 32
Hippocampal area CA2: properties and contribution to hippocampal function
Robert, V., Cassim, S., Chevaleyre, V., & Piskorowski, R. A. (2018) · Cell and Tissue Research · doi:10.1007/s00441-017-2769-7 · Cited by 33
Bygrave, A. M., Kilonzo, K., Kullmann, D. M., Bannerman, D. M., & Kätzel, D. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00835 · Cited by 35
Hasam‐Henderson, L. A., Gotti, G. C., Mishto, M., Klisch, C., Gerevich, Z., Geiger, J. R. P., & Kovács, R. (2018) · Scientific Reports · doi:10.1038/s41598-018-27830-2 · Cited by 34
Burket, J. A., Webb, J. D., & Deutsch, S. I. (2021) · Biomolecules · doi:10.3390/biom11081235 · Cited by 31
Regulation of Synapse Development byVgatDeletion from ErbB4-Positive Interneurons
Lin, T. W., Tan, Z., Barik, A., Yin, D., Brudvik, E., Wang, H., Xiong, W., & Mei, L. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.0669-17.2018 · Cited by 37
McKenna, M., Shackelford, D. B., Pontes, C., Ball, B. K., Gao, T., & Nance, E. A. (2021) · ACS Nano · doi:10.1021/acsnano.1c00394 · Cited by 32
Oxidative/Nitrosative Stress in Psychiatric Disorders: Are We There Yet?
O’Donnell, P., Do, K. Q., & Arango, C. (2014) · Schizophrenia Bulletin · doi:10.1093/schbul/sbu048 · Cited by 29
Self-citationJakovljević, A., Tucić, M., Blažíková, M., Korenić, A., Missirlis, Y. F., Stamenković, V., & Anđjus, P. R. (2021) · Cells · doi:10.3390/cells10061345 · Cited by 32
Net gain and loss: influence of natural rewards and drugs of abuse on perineuronal nets
Brown, T. E., & Sorg, B. A. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-022-01337-x · Cited by 25
Sexually dimorphic perineuronal nets in the rodent and primate reproductive circuit
Ciccarelli, A., Weijers, D., Kwan, W. C., Warner, C. E., Bourne, J. A., & Gross, C. T. (2021) · The Journal of Comparative Neurology · doi:10.1002/cne.25167 · Cited by 28
Perineuronal nets and GABAergic cells in the inferior colliculus of guinea pigs
Foster, N. L., Mellott, J. G., & Schofield, B. R. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2013.00053 · Cited by 30
Bucher, E., Collins, J. M., King, A. E., Vickers, J. C., & Kirkcaldie, M. (2021) · Brain Structure and Function · doi:10.1007/s00429-021-02327-3 · Cited by 31
Altered Relationship Between Parvalbumin and Perineuronal Nets in an Autism Model
Xia, D., Li, L., Yang, B., & Zhou, Q. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.597812 · Cited by 31
Klimczak, P., Rizzo, A., Castillo-Gómez, E., Pérez-Rando, M., Gramuntell, Y., Beltrán, M. A. C. S., & Nácher, J. (2021) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2021.733989 · Cited by 31
Mafi, A. M., Hofer, L. N., Russ, M. G., Young, J. W., & Mellott, J. G. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00027 · Cited by 25
Yang, X. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0117 · Cited by 31
Burstein, E. S. (2021) · CNS Drugs · doi:10.1007/s40263-021-00836-7 · Cited by 31
A postnatal molecular switch drives activity-dependent maturation of parvalbumin interneurons
Moissidis, M., Abbasova, L., Selten, M. M., Alis, R., Bernard, C., Domínguez-Canterla, Y., Oozeer, F., Qin, S., Kelly, A., Mòdol, L., et al. (2025) · Cell · doi:10.1016/j.cell.2025.06.029 · Cited by 38
Quantitative changes in perineuronal nets in development and posttraumatic condition
Lipachev, N., Arnst, N., Melnikova, A. A., Jäälinoja, H. T., Kochneva, A., Zhigalov, A., Kulesskaya, N., Aganov, A. V., Олегович, М. М., Rauvala, H., et al. (2019) · Journal of Molecular Histology · doi:10.1007/s10735-019-09818-y · Cited by 26
Genome-Wide Target Analyses of Otx2 Homeoprotein in Postnatal Cortex
Sakai, A., Nakato, R., Ling, Y., Hou, X., Hara, N., Iijima, T., Yanagawa, Y., Kuwano, R., Okuda, S., Shirahige, K., et al. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00307 · Cited by 30
Pinna, A., & Colasanti, A. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.689473 · Cited by 28
Sugitani, K., Egorova, D., Mizumoto, S., Nishio, S., Yamada, S., Kitagawa, H., Oshima, K., Nadano, D., Matsuda, T., & Miyata, S. (2021) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2020.129804 · Cited by 28
Mueller, A. L., Davis, A., Sovich, S., Carlson, S. S., & Robinson, F. R. (2016) · Neural Plasticity · doi:10.1155/2016/6021428 · Cited by 29
Liu, L., Zhang, Y., Men, S., Li, X., Hou, S., & Ju, J. (2023) · Hippocampus · doi:10.1002/hipo.23503 · Cited by 27
Lau, B. Y. B., Layo-Carris, D. E., Emery, B. A., Everett, M., Kumar, A., Stevenson, P. K., Reynolds, K. G., Cherosky, A., Bowyer, S.-A. H., Roth, S., et al. (2020) · eNeuro · doi:10.1523/eneuro.0500-19.2020 · Cited by 29
Acan downregulation in parvalbumin GABAergic cells reduces spontaneous recovery of fear memories
Lavertu-Jolin, M., Chattopadhyaya, B., Chehrazi, P., Carrier, D., Wünnemann, F., Leclerc, S., Dumouchel, F., Robertson, D. N., Affia, H., Saba, K., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02085-0 · Cited by 27
Perineuronal net, CSPG receptor and their regulation of neural plasticity.
Miao, Q., Ye, Q., & Zhang, X.-H. (2014) · PubMed · Cited by 27
Scheuer, T., Endesfelder, S., Brinke, E. A. D., Bührer, C., & Schmitz, T. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/8469756 · Cited by 25
Yamada, J., & Jinno, S. (2014) · The Journal of Comparative Neurology · doi:10.1002/cne.23712 · Cited by 27
Al-Amin, M. M., Sullivan, R., Kurniawan, N. D., & Burne, T. H. J. (2019) · Brain Structure and Function · doi:10.1007/s00429-019-01840-w · Cited by 27
Allgäuer, L., Cabungcal, J.-H., Yzydorczyk, C., Kim, Q., & Dwir, D. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02322-8 · Cited by 27
Self-citationBíró, L., Miskolczi, C., Szebik, H., Bruzsik, B., Varga, Z. K., Szente, L., Tóth, M., Halász, J., & Mikics, É. (2023) · Neurobiology of Stress · doi:10.1016/j.ynstr.2023.100546 · Cited by 28
Region-Specific Alterations of Perineuronal Net Expression in Postmortem Autism Brain Tissue
Brandenburg, C., & Blatt, G. J. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.838918 · Cited by 25
Orsini, C. A., Brown, T. E., Hodges, T. E., Alonso‐Caraballo, Y., Winstanley, C. A., & Becker, J. B. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.1378-22.2022 · Cited by 33
Potential of Cellular Therapy for ALS: Current Strategies and Future Prospects
Lin, T.-J., Cheng, K.-C., Wu, L.-Y., Lai, W.-Y., Ling, T., Kuo, Y., & Huang, Y. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.851613 · Cited by 26
Spinal Cord Injury and Loss of Cortical Inhibition
Benedetti, B., Weidenhammer, A., Reisinger, M., & Couillard‐Després, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105622 · Cited by 27
Kilonzo, V. W., Sweet, R. A., Glausier, J. R., & Pitts, M. W. (2020) · Schizophrenia Bulletin · doi:10.1093/schbul/sbaa082 · Cited by 25
Fujikawa, R., Yamada, J., & Jinno, S. (2020) · Schizophrenia Research · doi:10.1016/j.schres.2020.11.016 · Cited by 24
Forostyak, S., Forostyak, O., Kwok, J. C. F., Romanyuk, N., Řehořová, M., Kriška, J., Dayanithi, G., Raha‐Chowdhury, R., Jendelová, P., Anděrová, M., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249593 · Cited by 24
The role of parvalbumin interneuron dysfunction across neurodegenerative dementias
Smeralda, C. L., Pandit, S., Turrini, S., Reilly, J., Palmisano, A., Sprugnoli, G., Hampel, H. J., Benussi, A., Borroni, B., Press, D. Z., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102509 · Cited by 26
Khoueiry, C. E., Cabungcal, J.-H., Rovó, Z., Fournier, M., Kim, Q., & Steullet, P. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01425-2 · Cited by 22
Self-citationFunctional consequences of postnatal interventions in a mouse model of Fragile X syndrome
Rais, M., Lovelace, J. W., Shuai, X. S., Woodard, W., Bishay, S., Estrada, L., Sharma, A. R., Nguy, A. K., Kulinich, A. O., Pirbhoy, P. S., et al. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105577 · Cited by 25
Lee, B., Zhang, Y., Kim, Y., Kim, S., Lee, Y., & Han, K. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.04.016 · Cited by 26
Li, X., Wu, X., Lu, T., Kuang, C., Si, Y., Zheng, W., Li, Z., & Xue, Y.-X. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063412 · Cited by 28
The Role of Perineuronal Nets in Physiology and Disease: Insights from Recent Studies
Auer, S., Schicht, M., Hoffmann, L., Budday, S., Frischknecht, R., Blümcke, I., & Paulsen, F. P. (2025) · Cells · doi:10.3390/cells14050321 · Cited by 32
Igarashi, M., Takeuchi, K., & Sugiyama, S. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.10.001 · Cited by 22
Sex and region-specific effects of high fat diet on PNNs in obesity susceptible rats
Dingess, P. M., Zhang, Z., Sorg, B. A., Ferrario, C. R., & Brown, T. E. (2020) · Physiology & Behavior · doi:10.1016/j.physbeh.2020.112963 · Cited by 24
Holter, M. C., Hewitt, L. T., Nishimura, K. J., Knowles, S. J., Bjorklund, G. R., Shah, S., Fry, N., Rees, K. P., Gupta, T. A., Daniels, C. W., et al. (2020) · Cerebral Cortex · doi:10.1093/cercor/bhaa413 · Cited by 22
Jorgensen, E. T., Gonzalez, A. E., Harkness, J. H., Hegarty, D. M., Thakar, A., Burchi, D. J., Aadland, J. A., Aicher, S. A., Sorg, B. A., & Brown, T. E. (2020) · Addiction Biology · doi:10.1111/adb.12947 · Cited by 20
Alameda, L., Liu, Z., Sham, P. C., Aas, M., Trotta, G., Rodríguez, V., Forti, M. D., Stilo, S. A., Kandaswamy, R., Arango, C., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02044-9 · Cited by 24
Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA)
Witkin, J. M., Shafique, H. S., Cerne, R., Smith, J. L., Marini, A. M., Lipsky, R. H., & Delery, E. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108609 · Cited by 26
Sonnenschein, S. F., & Grace, A. A. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2021.1849144 · Cited by 23
Parvalbumin interneuron cell-to-network plasticity: mechanisms and therapeutic avenues
Hadler, M. D., Alle, H., & Geiger, J. R. P. (2024) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2024.04.003 · Cited by 21
Agnati, L. F., Marcoli, M., Maura, G., Woods, A. S., & Guidolin, D. (2018) · Journal of Neural Transmission · doi:10.1007/s00702-018-1855-7 · Cited by 22
Nicotinic regulation of experience-dependent plasticity in visual cortex
Sadahiro, M., Sajo, M., & Morishita, H. (2016) · Journal of Physiology-Paris · doi:10.1016/j.jphysparis.2016.11.003 · Cited by 22
Self-citationNetworks of blood proteins in the neuroimmunology of schizophrenia
Jeffries, C. D., Perkins, D. O., Fournier, M., Kim, Q., Cuénod, M., Khadimallah, I., Domenici, E., Addington, J., Bearden, C. E., Cadenhead, K. S., et al. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0158-y · Cited by 23
Apam-Castillejos, D. J., Tendilla‐Beltrán, H., Vázquez‐Roque, R. A., Vázquez-Hernández, A. J., Fuentes‐Medel, E., García‐Dolores, F., Díaz, A., & Flores, G. (2022) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2022.102166 · Cited by 21
van de Looij, Y., Larpin, C., Cabungcal, J.-H., Sanches, E. F., Toulotte, A., Kim, Q., & Sizonenko, S. V. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00046 · Cited by 21
Self-citationParvalbumin interneuron loss mediates repeated anesthesia-induced memory deficits in mice
Roque, P. S., Pérez, C. T., Hooshmandi, M., Wong, C., Eslamizade, M. J., Heshmati, S., Brown, N., Sharma, V. K., Lister, K. C., Goyon, V., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci159344 · Cited by 23
The Role of Parvalbumin Interneurons in Autism Spectrum Disorder
Yao, Y., & Li, Q. (2024) · Journal of Neuroscience Research · doi:10.1002/jnr.25391 · Cited by 20
Neuroanatomical Alterations in the CNTNAP2 Mouse Model of Autism Spectrum Disorder
Gandhi, T., Canepa, C. R., Adeyelu, T. T., Adeniyi, P. A., & Lee, C. C. (2023) · Brain Sciences · doi:10.3390/brainsci13060891 · Cited by 22
Hippocampal area CA2: interneuron disfunction during pathological states
Piskorowski, R. A., & Chevaleyre, V. (2023) · Frontiers in Neural Circuits · doi:10.3389/fncir.2023.1181032 · Cited by 22
Grieco, S. F., Johnston, K. G., Gao, P., Garduño, B. M., Tang, B., Yi, E., Sun, Y., Horwitz, G. D., Yu, Z., Holmes, T. C., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02153-5 · Cited by 18
Extracellular matrix abnormalities in the hippocampus of subjects with substance use disorder
Valeri, J., Stiplosek, C., O'Donovan, S. M., Sinclair, D., Grant, K. A., Bollavarapu, R., Platt, D. M., Stockmeier, C. A., Gisabella, B., & Pantazopoulos, H. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02833-y · Cited by 22
Modelling and Refining Neuronal Circuits with Guidance Cues: Involvement of Semaphorins
Limoni, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116111 · Cited by 18
Parvalbumin interneuron-derived tissue-type plasminogen activator shapes perineuronal net structure
Lépine, M., Douceau, S., Devienne, G. F., Prunotto, P., Lenoir, S., Regnauld, C., Pouettre, E., Piquet, J., Lebouvier, L., Hommet, Y., et al. (2022) · BMC Biology · doi:10.1186/s12915-022-01419-8 · Cited by 21
Hurley, M. M., Collica, S. C., Aston, S. A., Wiles, L. J., Weiner, R. C., Biswas, A., Bhasin, H., Sabir, A. I., Goodman, E. J., Purbey, R., et al. (2021) · Appetite · doi:10.1016/j.appet.2021.105666 · Cited by 17
Wang, T., Sinha, A. S., Akita, T., Yanagawa, Y., & Fukuda, A. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00284 · Cited by 19
Schiavone, S., Morgese, M. G., Bové, M., Colia, A. L., Maffione, A. B., Tucci, P., Trabace, L., & Cuomo, V. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.109750 · Cited by 19
Yamada, J., Ohgomori, T., & Jinno, S. (2017) · The Journal of Comparative Neurology · doi:10.1002/cne.24198 · Cited by 17
Nonneuronal contributions to synaptic function
Hodebourg, R., Scofield, M. D., Kalivas, P. W., & Kuhn, B. N. (2025) · Neuron · doi:10.1016/j.neuron.2025.04.004 · Cited by 19
Griffiths, B. B., Sahbaie, P., Rao, A. N., Arvola, O., Xu, L., Liang, D., Ouyang, Y., Clark, J. D., Giffard, R. G., & Stary, C. M. (2019) · NeuroMolecular Medicine · doi:10.1007/s12017-019-08532-y · Cited by 18
Gonzalez, A. E., Jorgensen, E. T., Ramos, J. D., Harkness, J. H., Aadland, J. A., Brown, T. E., & Sorg, B. A. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.932391 · Cited by 14
Czekus, C., Steullet, P., López, A. O., Bozic, I., Rusterholz, T., Bandarabadi, M., Kim, Q., & Herrera, C. G. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01700-w · Cited by 18
Self-citationYang, P., Davidson, J. O., Fowke, T. M., Galinsky, R., Wassink, G., Karunasinghe, R. N., Prasad, J. D., Ranasinghe, S., Green, C. R., Bennet, L., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186475 · Cited by 17
Cicanic, M., Edamatsu, M., Bekku, Y., Voříšek, I., Oohashi, T., & Vargová, L. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24136 · Cited by 18
Bozzelli, P. L., Caccavano, A., Avdoshina, V., Mocchetti, I., Wu, J., & Conant, K. E. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.113077 · Cited by 15
Trnski, S., Nikolić, B., Ilić, K., Drlje, M., Bobić‐Rasonja, M., Darmopil, S., Petanjek, Z., Hranilović, D., & Milošević, N. J. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.810980 · Cited by 16
Burket, J. A., Urbano, M. R., & Deutsch, S. I. (2017) · Clinical Neuropharmacology · doi:10.1097/wnf.0000000000000209 · Cited by 17
Increased extracellular clusterin in the prefrontal cortex in schizophrenia
Athanas, K. M., Mauney, S. A., & Woo, T.-U. W. (2015) · Schizophrenia Research · doi:10.1016/j.schres.2015.10.002 · Cited by 16
Sonnenschein, S. F., & Grace, A. (2021) · Schizophrenia bulletin · doi:10.1093/schbul/sbab047 · Cited by 15
Briones, B. A., Pitcher, M. N., Fleming, W., Libby, A., Diethorn, E. J., Haye, A. E., MacDowell, C. J., Zych, A. D., Waters, R. C., Buschman, T. J., et al. (2021) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2021.11.005 · Cited by 15
Ueno, H., Suemitsu, S., Murakami, S., Kitamura, N., Wani, K., Okamoto, M., Aoki, S., & Ishihara, T. (2017) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2017.08.003 · Cited by 18
Increased MMP-9 levels with strain-dependent stress resilience and tunnel handling in mice
Kennedy-Wood, K., Ng, C. A. S., Alaiyed, S., Foley, P. L., & Conant, K. E. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113288 · Cited by 15
Anderson, M. D., Paylor, J. W., Scott, G. A., Greba, Q., Winship, I. R., & Howland, J. G. (2020) · Learning & Memory · doi:10.1101/lm.050245.119 · Cited by 16
Kolář, D., Krajčovič, B., Kletečková, L., Kunčická, D., Valeš, K., & Brožka, H. (2023) · Schizophrenia Bulletin · doi:10.1093/schbul/sbad066 · Cited by 17
Mafi, A. M., Russ, M. G., Hofer, L. N., Pham, V. Q., Young, J. W., & Mellott, J. G. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.04.001 · Cited by 14
Guarque‐Chabrera, J., Sanchez-Hernandez, A., Ibáñez-Marín, P., Eixea, I. M., & Miquel, M. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109210 · Cited by 14
Experience‐dependent transcriptional regulation in juvenile brain development
Sakai, A., & Sugiyama, S. (2018) · Development Growth & Differentiation · doi:10.1111/dgd.12571 · Cited by 15
Grycz, K., Głowacka, A., Ji, B., Krzywdzińska, K., Charzyńska, A., Czarkowska‐Bauch, J., Gajewska‐Woźniak, O., & Skup, M. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114098 · Cited by 16
Dynamic regulation of the extracellular matrix in reward memory processes: a question of time
Valeri, J., Gisabella, B., & Pantazopoulos, H. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1208974 · Cited by 14
Woo, A. M., & Sontheimer, H. W. (2023) · Frontiers in Molecular Medicine · doi:10.3389/fmmed.2023.1198021 · Cited by 17
Metadata
- Authors
- Cabungcal, J.-H., Steullet, P., Morishita, H., Kraftsik, R., Cuenod, M., Hensch, T. K., & Do, K. Q.
- Affiliations
- Centre Hospitalier Universitaire Vaudois (CH)
- Boston Children's Hospital (US)
- University of Lausanne (CH)
- Center for Psychiatric Neuroscience, Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1008 Prilly-Lausanne, Switzerland;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-05-13
- Volume
- 110
- Issue
- 22
- Pages
- 9130-9135
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3670388
- OpenAlex
- W2032089725
- Semantic Scholar
- 072380ff105234dbb5c1f2b91779ad413aea8b2f
- Cited by
- 512
- References
- 60
- Citations by year
- 2026: 41 · 2025: 42 · 2024: 41 · 2023: 42 · 2022: 46 · 2021: 46 · 2020: 38 · 2019: 35 · 2018: 52 · 2017: 39 · 2016: 31 · 2015: 29 · 2014: 25 · 2013: 4
- FWCI
- 13.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (125759, 116689)
- National Institutes of Health (DP1OD003699)
- National Institute of Mental Health (P50MH094271)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- perineuronal nets, fast-spiking interneurons, parvalbumin, oxidative stress, schizophrenia, redox imbalance, reactive oxygen species, antioxidant defense, neuronal synchronization, inhibitory circuits, extracellular matrix degradation
- MeSH terms
- Analysis of Variance, Animals, Crosses, Genetic, Evoked Potentials, Extracellular Matrix, Glutamate-Cysteine Ligase, Image Processing, Computer-Assisted, Immunohistochemistry, Interneurons, Mice, Inbred C57BL, Microscopy, Fluorescence, Parvalbumins, Schizophrenia, Mice, Knockout, Oxidative Stress, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
