Perineuronal nets protect fast-spiking interneurons against oxidative stress

Fast-spiking properties impose high metabolic demand and increased mitochondrial density, rendering PV cells, but not other interneurons such as calretinin and calbindin cells, particularly sensitive to oxidative stress.

“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).”

• cites [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. sourceCould not verify

  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)

  Experimental — accuracy not yet measured

The antioxidant N-acetylcysteine prevents the GBR-induced PV-cell defect in Gclm KO mice.

“Furthermore, the antioxidant N-acetylcysteine prevents the GBRinduced PV-cell defect in Gclm KO mice (3).”

• cites [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. sourceCould not verify

  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)

  Experimental — accuracy not yet measured

Across multiple neuropsychiatric disorders, including autism, schizophrenia, and bipolar disorder, the developmental gene expression program in PV cells is immature.

“Across multiple neuropsychiatric disorders, including autism, schizophrenia, and bipolar disorder, the developmental gene expression program in PV cells is instead immature (54).”

• cites [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. sourcePartly supported

  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)

  Experimental — accuracy not yet measured

ROS breaks down two PNN components, hyaluronan and chondroitin sulfate.

“ROS is known to break down two PNN components, hyaluronan and chondroitin sulfate (47).”

• cites [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. sourceCould not verify

  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)

  Experimental — accuracy not yet measured

Oxidative stress may contribute to the slow emergence of psychoses by mistiming key windows of brain development.

“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.”

• cites [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. sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites [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. sourceCould not verify

  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)

  Experimental — accuracy not yet measured

PNNs are themselves sensitive to excess oxidative stress.

“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.”

PV cells enwrapped with mature PNNs are better protected than immature PV cells surrounded by less-condensed PNNs.

“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.”

There is an inverse relationship between the robustness of PNNs around PV cells and the degree of intracellular oxidative stress they display.

“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).”

PNNs are themselves sensitive to excessive redox dysregulation.

“PNNs Are Themselves Sensitive to Excessive Redox Dysregulation.”

In P90 Gclm KO mice, the ACC displayed significantly more oxidative stress than WT, as revealed by 8-oxo-dG.

“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].”

Degradation of mature PNNs renders PV cells more susceptible to oxidative stress.

“Degradation of Mature PNNs Renders PV Cells More Susceptible to Oxidative Stress.”

In P90 Gclm KO mice, beta and gamma oscillations were not significantly different between genotypes.

“In the ACC of P90 mice that showed no deficit in the number of PV immunoreactive cells, these oscillations were not significantly different between genotypes (Fig. S2).”

This level of oxidative stress was insufficient to significantly affect PV cells or PNNs in P90 Gclm KO mice.

“This level of oxidative stress was, however, insufficient to significantly affect PV cells [number of PV immunoreactive cells: 71.8 ± 12.6 (KO) vs. 71.3± 12.8 (WT)] or PNNs labeled with the lectin Wisteria floribunda agglutinin (WFA).”

WFA-labeled PNNs were not affected in P180 Gclm KO mice.

“In contrast, WFA-labeled PNNs were not affected (Fig. 1 A and B).”

The proportion of PV cells surrounded by PNNs was higher in P180 Gclm KO mice than in age-matched WT mice.

“The proportion of PV cells surrounded by PNNs was consequently higher in P180 Gclm KO mice than in age-matched WT mice (Fig. 1 A and B).”

In both PBS-treated and GBR-treated mice, WFA labeling in the ChABC-injected ACC was faint and significantly weaker than in sham ACC.

“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).”

Immature PV cells bearing less-condensed PNNs are more vulnerable to oxidative stress.

“Immature PV Cells Bearing Less-Condensed PNNs Are More Vulnerable to Oxidative Stress.”

In P180 Gclm KO mice, ACC displayed significantly weaker beta and gamma oscillations compared with age-matched WT mice.

“In contrast, the ACC of P180 Gclm KO mice, which contained fewer PV immunoreactive cells (Fig. 1B), displayed significantly weaker β and γ oscillations compared with the ACC of age-matched WT mice (Fig. 1 C and D).”

GBR-induced oxidative stress was accompanied by a decreased number of PV immunoreactive cells at P20, but not at P90.

“GBR-induced oxidative stress was accompanied by a decreased number of PV immunoreactive cells at P20, but not at P90 (Fig. 2B).”

In P20 Gclm KO mice, WFA-labeled PNNs had not yet fully condensed compared with those at P90.

“In P20 Gclm KO mice, the WFA-labeled PNNs had not yet fully condensed compared with those at P90 (Fig. 2A).”

PV-Gclc KO mice displayed much stronger 8-oxo-dG labeling within PV cells compared with PV-Gclc WT mice or Gclm KO mice.

“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).”

In cortical layers enriched in PV cells, some cells displayed strong 8-oxo-dG labeling, although they were neither PV immunoreactive nor enwrapped by WFA-labeled PNNs.

“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.”

The degree of oxidative stress per PV cell varied with PNN density surrounding it, yielding a significant inverse correlation.

“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).”

GBR-generated ROS were not sufficient to elicit oxidative stress in WT mice with an intact antioxidant system.

“In contrast, GBR-generated ROS were not sufficient to elicit oxidative stress in WT mice with an intact antioxidant system (Fig. S3).”

GBR-induced oxidative stress only affects PV cells in P20 Gclm KO mice.

“(B) GBR-induced oxidative stress only affects PV cells in P20 Gclm KO.”

The 8-oxo-dG labeling after GBR treatment was significantly higher in ChABC-injected than in sham ACC.

“The 8-oxo-dG labeling after GBR treatment was likewise significantly higher in ChABC-injected than in sham ACC (Fig. 5C).”

WFA-labeled PNNs are not affected in KO mice.

“(Center) WFA-labeled PNNs are not affected in KO mice.”

WFA-labeled PNNs in P20 Gclm KO mice are not fully developed around PV cells compared with P90 mice.

“(A) WFA-labeled PNNs in P20 Gclm KO mice are not fully developed around PV cells compared with P90 mice (n = 5 per group).”

The percentage of PV immunoreactive cells enwrapped by WFA-labeled PNNs is higher in KO mice.

“(Right) percentage of PV immunoreactive cells enwrapped by WFA-labeled PNNs is higher in KO mice”

Local neuronal synchronization in ACC slices is reduced in P180 KO mice.

“(C) Local neuronal synchronization in ACC slices (induced by carbachol, kainic acid, and quinpirole) is reduced in P180 KO mice.”

PNN degradation by ChABC exacerbated the GBR-induced increase of 8-oxo-dG labeling throughout the ACC, not just in PV cells.

“Notably, PNN degradation by ChABC exacerbated the GBR-induced increase of 8-oxo-dG labeling throughout the ACC, not just in PV cells (Fig. 5C).”

In GBR-treated Gclm KO mice, the power of oscillations tended to be weaker in the ChABC-injected side compared with sham ACC.

“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).”

In control PBS-treated Gclm KO mice, the power of oscillations tended to be stronger in the ChABC-injected side compared with contralateral sham ACC.

“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).”

The power of β- and γ-oscillations is weaker in KO slices than in WT slices.

“The power of β-(13-28 Hz; Left) and γ-oscillations (30-60 Hz; Right) is weaker in KO (n = 11) vs. WT slices (n = 15).”

Cortical injection of ChABC fully removed labeling by the lectin WFA.

“Cortical injection of ChABC fully removed labeling by the lectin WFA”

Fast rhythmic oscillations reflecting neuronal synchronization were clearly altered in slices of ChABC-injected ACC from P90 GBR-treated Gclm KO mice.

“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].”

WFA-labeled PNNs themselves suffer from excessive oxidative stress or severe redox dysregulation.

“Conversely, we also show that WFAlabeled PNNs themselves suffer from excessive oxidative stress or severe redox dysregulation.”

There is an inverse relationship between the number of voxels stained with WFA (PNNs) and 8-oxo-dG associated with each PV cell.

“Quantile density contours and linear regression plot illustrate the inverse relationship between the number of voxels stained with WFA (PNNs) and 8-oxo-dG associated with each PV cell.”

GBR treatment generates significant additional oxidative stress in the ACC of P20 and P90 Gclm KO mice.

“(C) GBR treatment generates significant additional oxidative stress in the ACC of P20 and P90 Gclm KO mice (n = 4 per group).”

PNN degradation did not affect the number of calbindin- and calretinin-immunoreactive cells when subjected to GBR-induced oxidative stress.

“PNN degradation did not, however, affect the number of calbindin-and calretininimmunoreactive cells when subjected to GBR-induced oxidative stress (Fig. S6).”

Stereological quantification reveals fewer PV immunoreactive cells in KO mice than in WT mice (n = 6 per group).

“(Left) stereological quantification reveals fewer PV immunoreactive cells in KO mice than in WT mice (n = 6 per group).”

Only GBR caused a significant decrease in the number of PV immunoreactive cells in the ChABC-injected ACC compared with the contralateral side.

“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 effect of PNN degradation on the oscillation power depends on the treatment (PBS vs. GBR), with a significant interaction between PNN status and treatment.

“The effect of PNN degradation on the oscillation power depends on the treatment (PBS vs. GBR): significant interaction (P = 0.039, multivariate analysis) between PNN status in ACC (ChABC-vs.sham-injected) and treatment (PBS vs. GBR).”

The number of PV immunoreactive cells is not significantly different in GBR-treated WT and KO mice.

“(B) Quantification (n = 5 per group) shows that the number of PV immunoreactive cells is not significantly different in GBR-treated WT and KO mice (Left).”

The 8-oxo-dG signal is stronger in ChABC-injected ACC after GBR treatment.

“The 8-oxo-dG signal is stronger in ChABC-injected ACC after GBR treatment.”

Redox dysregulation restricted to PV cells (PV-Gclc KO mice) leads to strong 8-oxo-dG signals within PV cells of the ACC.

“(A) Redox dysregulation restricted to PV cells (PV-Gclc KO mice) leads to strong 8-oxo-dG signals within PV cells of the ACC.”

GBR significantly reduces WFA labeling in KO compared with WT mice.

“However, GBR significantly reduces WFA labeling in KO compared with WT mice (Right).”

In PBS-treated mice, oscillations tend to be higher in ChABC-injected compared with contralateral sham ACC.

“In PBS-treated mice, oscillations tend to be higher in ChABC-injected compared with contralateral sham ACC (9 of 11 slices) (E).”

Quantification shows higher 8-oxo-dG labeling within the ACC and within PV cells of PV-Gclc KO compared with PV-Gclc WT mice.

“(B) Quantification shows higher 8-oxo-dG labeling within the ACC (Left) and within PV cells (percentage PV colocalized with 8-oxo-dG; Right) of PV-Gclc KO compared with PV-Gclc WT mice (n = 5 per group).”

In GBR-treated mice, oscillations tend to be weaker in ChABC-injected compared with contralateral sham ACC.

“In contrast, in GBR-treated mice, oscillations tend to be weaker in ChABC-injected compared with contralateral sham ACC (4 of 7 slices) (F).”

The protection might reflect a balance between the oxidative burden on PNN degradation and the capacity of the system to maintain the nets.

“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.”

• Also stated in: § Discussion · hedged

  “PV cell protection might then reflect a balance between the oxidative burden on PNN degradation and the capacity of PV cells and nearby glial or neuronal cells to maintain the extracellular nets.”

Perineuronal nets (PNNs) play a critical role in protection against 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.”

Abnormal PNNs, as observed in the postmortem patient brain, may underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.

“Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.”

Gclm knockout (KO) mice do not express the modulatory subunit of Gclm, the rate-limiting enzyme of GSH synthesis.

“These mice do not express the modulatory subunit of the glutamate cysteine ligase (Gclm, ref. 36), the rate-limiting enzyme of GSH synthesis.”

• cites [36] 36. Morawski M, Brückner MK, Riederer P, Brückner G, Arendt T (2004) Perineuronal nets potentially protect against oxidative stress. Exp Neurol 188(2):309-315. sourceNot checked — no full text of the source

PV cells enwrapped by well-formed PNNs displayed less oxidative stress.

“Thus, PV cells enwrapped by well-formed PNNs displayed less oxidative stress.”

A large population of WFA-positive PNNs is associated with PV cells.

“A large population of WFA-positive PNNs is associated with PV cells (38).”

• cites [38] 38. Yang Y, et al. (2002) Initial characterization of the glutamate-cysteine ligase modifier subunit Gclm(-/-) knockout mouse. Novel model system for a severely compromised oxidative stress response. J Biol Chem 277(51):49446-49452. sourceNot checked — no full text of the source

PNNs protect mature PV cells against oxidative stress.

“In this study, we provide experimental evidence that the PNNs protect mature PV cells against oxidative stress.”

• Also stated in: § Discussion · boosted

  “Our study provides experimental evidence that intact and mature WFA-labeled PNNs protect fast-spiking PV cells against oxidative stress.”

GBR treatment partially mimics the pronounced prefrontal dopamine release during psychosocial stress.

“This pharmacological approach partially mimics the pronounced prefrontal dopamine release during psychosocial stress (41,42).”

• cites [41] 41. Cadet JL, Brannock C (1998) Free radicals and the pathobiology of brain dopamine systems. Neurochem Int 32(2):117-131. sourceNot checked — no full text of the source
• cites [42] 42. Rabinovic AD, Hastings TG (1998) Role of endogenous glutathione in the oxidation of dopamine. J Neurochem 71(5):2071-2078. sourceNot checked — no full text of the source

Gclm KO mice have low brain GSH levels (~30% of WT levels).

“These Gclm knockout (KO) mice have low brain GSH levels (∼30% of WT levels) (37)”

• cites [37] 37. Suttkus A, Rohn S, Jäger C, Arendt T, Morawski M (2012) Neuroprotection against iron-induced cell death by perineuronal nets -an in vivo analysis of oxidative stress. Am J Neurodegener Dis 1(2):122-129.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Abnormal neuronal synchrony in gamma and beta bands during sensory and cognitive processing tasks indicates PV cell network dysfunction in schizophrenia.

“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.”

• cites (12)(13)(14)(15)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

PV-cell impairment in preweaning GBR-treated KO mice was associated with induced oxidative stress and not with other dopamine-mediated mechanisms.

“Because GBR neither significantly induced 8-oxo-dG label- ing nor altered PV immunoreactivity in WT mice at either age (Fig. S3), this indicates that PV-cell impairment in preweaning GBR-treated KO mice was associated with the induced oxidative stress and not with other dopamine-mediated mechanisms.”

Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder.

“Postmortem studies reveal PV-cell anomalies in individuals with schizophrenia or bipolar disorder (9)(10)(11).”

• cites (9)(10)(11)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

As Gclm KO mice aged further, the chronic deficit in GSH eventually led to PV-cell impairment.

“However, as Gclm KO mice aged further, the chronic deficit in GSH eventually led to PV-cell impairment.”

When most fast-spiking PV cells mature, they become enwrapped by aggrecan-enriched PNNs.

“When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs).”

• cites [30] 30. Do KQ, Cabungcal JH, Frank A, Steullet P, Cuenod M (2009) Redox dysregulation, neurodevelopment, and schizophrenia. Curr Opin Neurobiol 19(2):220-230.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

ChABC injection efficiently degraded PNNs unilaterally, as verified 2 d postinjection by the absence of WFA labeling in the treated ACC.

“ChABC injection efficiently degraded PNNs unilaterally, as verified 2 d postinjection by the absence of WFA labeling in the treated ACC (Fig. S5).”

Psychosocial stresses during brain development, when combined with GSH dysregulation, could result in excess ROS and oxidative damage, leading to progressive structural and functional connectopathy.

“Psychosocial stresses during brain development could result, when combined with GSH dysregulation, in an excess of ROS and oxidative damage, leading to progressive structural and functional connectopathy.”

• AssumptionRests on an assumption: Severe life event stresses, through activation of the hypothalamic-pituitary-adrenal axis, induce release of dopamine, whose catabolism generates ROS.

Chondroitin sulfate decreases production of ROS generated by H2O2 or mitochondrial disruption by induction of heme oxygenase-1 through PI3K/Akt pathway.

“Chondroitin sulfate has further been shown to decrease the production of ROS generated by H 2 O 2 or mitochondrial disruption by induction of the antioxidant enzyme heme oxygenase-1 through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway (45).”

• cites [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. sourceNot checked — no full text of the source

Excessive ROS production, generated during strong environmental insults, and particularly in at-risk individuals for redox dysregulation, will have a potent effect on fast-spiking cells bearing immature or abnormal PNNs.

“Taken together, excessive ROS production, generated during strong environmental insults, and particularly in at-risk individuals for redox dysregulation, will have a potent effect on fastspiking cells bearing immature or abnormal PNNs.”

PV cells enwrapped with well-formed WFA-labeled PNNs, but not PV cells lacking WFA-labeled PNNs, are protected against long-lasting chronic redox dysregulation (as in P180 Gclm KO mice).

“This can explain our observation that PV cells enwrapped with well-formed WFA-labeled PNNs, but not PV cells lacking WFA-labeled PNNs, are protected against a longlasting chronic redox dysregulation (as in P180 Gclm KO mice).”

Our data are directly relevant to anomalies of PV-cell networks observed in neuropsychiatric disorders.

“Our data are thus directly relevant to the anomalies of PV-cell networks observed in these disorders.”

Mature PNNs protect PV cells from oxidative stress.

“Fig. 2. Mature PNNs protect PV cells from oxidative stress.”

A genetic association has been found between schizophrenia and the gene B3GAT2, involved in biosynthesis of HNK-1 carbohydrate epitope of tenascin, a major constituent of PNNs.

“Moreover, a genetic association has been found between schizophrenia and the gene B3GAT2, which is involved in biosynthesis of the human natural killer-1 (HNK-1) carbohydrate epitope of tenascin, a major constituent of PNNs (51).”

• cites [51] 51. Harris NG, Mironova YA, Hovda DA, Sutton RL (2010) Pericontusion axon sprouting is spatially and temporally consistent with a growth-permissive environment after traumatic brain injury. J Neuropathol Exp Neurol 69(2):139-154. sourceNot checked — no full text of the source

PNNs are neuroprotective.

“Our work provides experimental support to observations suggesting that PNNs are neuroprotective (34,35).”

• cites [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. sourceNot checked — no full text of the source
• cites [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.Not checked — no full text of the source

The higher susceptibility of PV cells to oxidative stress and to ROS in preweaning compared with adult mice might be related to the lack of fully condensed PNNs around immature PV cells.

“The higher susceptibility of PV cells to oxidative stress (this study) and to ROS (5) in preweaning compared with adult mice might also be related to the lack of fully condensed PNNs around immature PV cells.”

Mature PNNs specifically protect PV cells from additional oxidative stress.

“This demonstrates that mature PNNs specifically protect PV cells from additional oxidative stress.”

PNNs chelate iron through their poly-anionic nature, thereby limiting formation of iron-generated reactive hydrogen radicals.

“Through their poly-anionic nature, PNNs chelate iron (43), thereby limiting the formation of iron-generated reactive hydrogen radicals.”

• cites [43] 43. Feenstra MG, Vogel M, Botterblom MH, Joosten RN, de Bruin JP (2001) Dopamine and noradrenaline efflux in the rat prefrontal cortex after classical aversive conditioning to an auditory cue. Eur J Neurosci 13(5):1051-1054. sourceNot checked — no full text of the source

PV cell protection might reflect a balance between oxidative burden on PNN degradation and capacity of PV cells and nearby glial or neuronal cells to maintain the extracellular nets.

“PV cell protection might then reflect a balance between the oxidative burden on PNN degradation and the capacity of PV cells and nearby glial or neuronal cells to maintain the extracellular nets.”

The affected PV cells were those lacking PNNs.

“suggesting that the affected PV cells were those lacking PNNs.”

PV cells and their PNNs are sensitive to cell-autonomous redox dysregulation.

“Fig. 4. PV cells and their PNNs are sensitive to cell-autonomous redox dysregulation.”

PNN removal by ChABC renders PV cells vulnerable to oxidative stress.

“Fig. 5. PNN removal by ChABC renders PV cells vulnerable to oxidative stress.”

PNNs are sensitive to additional oxidative stress in Gclm KO mice.

“Fig. 3. PNNs are sensitive to additional oxidative stress in Gclm KO mice.”