Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons
Open accessAbstract
Background Oxidative stress and the specific impairment of perisomatic gamma-aminobutyric acid circuits are hallmarks of the schizophrenic brain and its animal models. Proper maturation of these fast-spiking inhibitory interneurons normally defines critical periods of experience-dependent cortical plasticity.Methods Here, we linked these processes by genetically inducing a redox dysregulation restricted to such parvalbumin-positive cells and examined the impact on critical period plasticity using the visual system as a model (3-6 mice/group).Results Oxidative stress was accompanied by a significant loss of perineuronal nets, which normally enwrap mature fast-spiking cells to limit adult plasticity. Accordingly, the neocortex remained plastic even beyond the peak of its natural critical period. These effects were not seen when redox dysregulation was targeted in excitatory principal cells.Conclusions A cell-specific regulation of redox state thus balances plasticity and stability of cortical networks. Mistimed developmental trajectories of brain plasticity may underlie, in part, the pathophysiology of mental illness. Such prolonged developmental plasticity may, in turn, offer a therapeutic opportunity for cognitive interventions targeting brain plasticity in schizophrenia.
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- Findingown data
The effects of redox dysregulation on plasticity were not seen when the dysregulation was targeted to excitatory principal cells.
“These effects were not seen when redox dysregulation was targeted in excitatory principal cells.”
Quote in the paperSubstantial claim - Findingown data
The percentage of PV cells bearing PNNs was reduced in PV-Gclc KO mice.
“the percentage of PV-cells bearing PNNs was also reduced (Figure 2D).”
Quote in the paperSubstantial claim - Findingown data
Conditional deletion of Gclc in PV interneurons produced progressive Gclc deletion in cortical PV cells, from 34% at P20 to 70% in adulthood (>P50).
“This yielded a progressive Gclc deletion in cortical PV-cells from 34% at postnatal day P20 to 70% in adulthood (>P50), as evaluated by double in situ hybridization for Gclc and Cre mRNA (Figure 1B,C).”
Quote in the paperSubstantial claim - Findingown data
The PV-cell-specific Gclc manipulation did not cause myelin deficits typically observed upon global redox dysregulation.
“The cell-specific manipulation was subtle and did not cause myelin deficits (Figure 1D,E) typically observed upon global redox dysregulation (3, 37).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3] Do, 2009, Redox dysregulation, neurodevelopment, and schizophrenia, Curr Opin Neurobiol source
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- cites [37] Do, 2012, Redox dysregulation affects proliferation, differentiation of oligodendrocyte progenitors and myelination: Relevance to dysconnectivity in schizophrenia, Biol Psychiatry
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- Findingown data
In PV-Gclc KO mice, oxidative stress was accompanied by a significant loss of perineuronal nets.
“Oxidative stress was accompanied by a significant loss of perineuronal nets”
Quote in the paperSubstantial claim
- Findingown data
A cell-autonomous enhancement of oxidative stress was observed in 69% of PV cells in PV-Gclc KO mice, as measured by 8-oxo-dG staining.
“Instead, a cell-autonomous enhancement of oxidative stress was observed in the majority (69%) of PV-cells when staining for a product of mitochondrial DNA oxidation, 8-oxo-7,8-dihydro-20-deoxyguanine (8-oxo-dG) (Figure 2A,B).”
Quote in the paperSubstantial claim - Findingown data
In the primary visual cortex of PV-Gclc KO mice, there were significantly fewer PV-immunoreactive cells and PNNs, as revealed by WFA staining.
“In the primary visual cortex of PV-Gclc KO mice, we observed significantly fewer PV-immunoreactive cells and PNNs, as revealed by WFA staining (Figure 2).”
Quote in the paperSubstantial claim - Findingreasoning
The neocortex of PV-Gclc KO mice remained plastic beyond the peak of its natural critical period.
“Accordingly, the neocortex remained plastic even beyond the peak of its natural critical period.”
Quote in the paperSubstantial claim - Findingown data
A mild activation of microglia was observed by CD68 staining in PV-Gclc KO mice.
“In fact, a mild activation of microglia was observed by CD68 staining (Figure 3A,B).”
Quote in the paperNot a substantial claim - Findingreasoning
The percentage of Otx2+/PV+ cells was significantly reduced in PV-Gclc KO mice, especially in cells enwrapped with PNNs.
“Consistent with this, the percentage of Otx2+/PV+ cells was significantly reduced in PV-Gclc KO mice, especially in those cells enwrapped with PNNs (Supplemental Figure S3).”
Quote in the paperSubstantial claim - Findingown data
PV-Gclc KO mice exhibited a significant loss of perisomatic PV+ puncta surrounding target pyramidal cell bodies in layer 2/3 of adult visual cortex.
“PV-Gclc KO mice further exhibited a significant loss of perisomatic PV+ puncta surrounding their target pyramidal cell bodies in layer 2/3 of adult visual cortex (Supplemental Figure S1).”
Quote in the paperSubstantial claim - Findingown data
There was no indication of neurodegeneration by Fluoro Jade C staining in PV-Gclc KO mice.
“Instead, there was no indication of neurodegeneration by Fluoro Jade C staining”
Quote in the paperSubstantial claim - Findingown data
In younger PV-Gclc KO mice during the natural critical period, there was no difference from WT plasticity levels.
“Consistent with a limited Gclc deletion in younger KO mice (Figure 1C) during the natural critical period, there was no difference from WT plasticity levels at that age (Supplemental Figure S7; CBI after 4 day MD = 0.49 in PV-Gclc KO vs. 0.51 in WT; p>0.2, n=3 mice each).”
Quote in the paperSubstantial claim - Findingown data
Immunoreactivity for PV and PNNs remained intact in the adult visual cortex of CamK2-Gclc KO mice.
“In contrast, immunoreactivity for PV and PNNs remained intact in the adult visual cortex of CamK2-Gclc KO mice (Supplemental Figure S4 and S5).”
Quote in the paperSubstantial claim - Findingown data
In PV-Gclc KO mice with majority of PV cells lacking Gclc by P50, short-term (4 day) monocular deprivation continued to yield a significant shift away from the deprived contralateral eye.
“When the majority of PV-cells lacked Gclc gene expression by this age in our conditional mutant mice (Figure 1A), extracellular single-unit recording continued to yield a significant shift away from the deprived, contralateral eye following short-term (4 day) monocular deprivation (Figure 4B,C,E)”
Quote in the paperSubstantial claim - Findingown data
The contralateral bias index differed significantly between PV-Gclc KO and WT mice (0.57 vs 0.68; age P54-P63; p<0.001).
“The contralateral bias index (CBI) differed significantly between genotypes (0.57 in KO vs. 0.68 in WT; age range between P54 and P63, p<0.001).”
Quote in the paperSubstantial claim - Findingown data
The enhanced plasticity in PV-Gclc KO mice past the peak of the critical period was not corrected by concurrent administration of Diazepam.
“This enhanced plasticity in PV-Gclc KO mice past the peak of the critical period was not corrected by concurrent administration of the benzodiazepine Diazepam (Supplemental Figure S6)”
Quote in the paperSubstantial claim - Premisecitation
Compromised PNNs prevent persistent uptake of Otx2 homeoprotein into enwrapped PV cells needed for their maturation, including PNN maintenance.
“Compromised PNNs prevent the persistent uptake of Otx2 homeoprotein into the enwrapped PV-cells needed for their maturation (including PNN maintenance itself) (27, 40, 41).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [27] Sugiyama, 2008, Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity, Cell source
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- cites [40] Miyata, 2012, Persistent cortical plasticity by upregulation of chondroitin 6-sulfation, Nat Neurosci source
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- cites [41] Beurdeley, 2012, Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex, J Neurosci source
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- Premisecitation
Disruption of excitatory-inhibitory balance shifts the timing and quality of critical period development in primary visual cortex.
“Accordingly, disruption of E-I balance powerfully shifts the timing and quality of critical period development, as seen in the primary visual cortex (V1) (27–29).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [27] Sugiyama, 2008, Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity, Cell source
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- cites [28] Fagiolini, 2000, Inhibitory threshold for critical-period activation in primary visual cortex, Nature source
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- cites [29] Morishita, 2010, Lynx1, a cholinergic brake, limits plasticity in adult visual cortex, Science source
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- Premisecitation
Redox dysregulation, an imbalance between oxidative stress and antioxidant defense, may contribute to schizophrenia pathogenesis.
“Mounting evidence also indicates that “redox dysregulation,” an imbalance between oxidative stress and antioxidant defense systems, may play a role in the pathogenesis (reviewed in ref. (3)).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Do, 2009, Redox dysregulation, neurodevelopment, and schizophrenia, Curr Opin Neurobiol source
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- Interpretationreasoning
Mis-timed developmental trajectories of brain plasticity may underlie in part the pathophysiology of mental illness.
“Mis-timed developmental trajectories of brain plasticity may underlie in part the pathophysiology of mental illness.”
Quote in the paperSubstantial claim - Premisecitation
Postnatal maturation of parvalbumin-positive GABA neurons defines critical periods of experience-dependent cortical plasticity.
“Notably, the postnatal maturation of PV-positive GABA neurons has been found to define critical periods of experience-dependent cortical plasticity (26).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Hensch, 2005, Critical period plasticity in local cortical circuits, Nat Rev Neurosci source
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- Interpretationcitation
The fast-spiking interneuron defects in redox models are consistent with physiological consequences on excitatory-inhibitory circuit balance during neurodevelopment.
“consistent with physiological consequences on excitatory-inhibitory (E–I) circuit balance during neurodevelopment.”
Quote in the paperSubstantial claim - Interpretationown data
Cell-specific regulation of redox state balances plasticity and stability of cortical networks.
“A cell-specific regulation of redox state thus balances plasticity and stability of cortical networks.”
Quote in the paperSubstantial claim - Premisecitation
Animal models with globally disrupted redox state show defects in fast-spiking interneurons.
“Animal models of globally disrupted redox state exhibit defects in fast-spiking interneurons (16, 23, 25)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [16] Steullet, 2010, Redox dysregulation affects the ventral but not dorsal hippocampus: Impairment of parvalbumin neurons, gamma oscillations, and related behaviors, J Neurosci source
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- cites [23] Behrens, 2007, Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase, Science source
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- cites [25] Cabungcal, 2013, Early-life insults impair parvalbumin interneurons via oxidative stress: Reversal by N-acetylcysteine, Biol Psychiatry source
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- Premisecitation
High metabolic demands make fast-spiking interneurons particularly vulnerable to oxidative stress.
“High metabolic demands render fast-spiking interneurons particularly vulnerable to oxidative stress (23).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Behrens, 2007, Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase, Science source
Not checked in the free run.
- Interpretationown data
The massive microglial activation and neurodegeneration in CamK2-Gclc KO mice indicate a robust, nonspecific response to cellular stress of any origin.
“indicating that this is a robust, nonspecific response to cellular stress of any origin.”
Quote in the paperSubstantial claim - Premisecitation
PNN disruption prevents persistent uptake of Otx2 homeoprotein into enwrapped PV cells required for their maintenance.
“Second, PNN disruption prevents the persistent uptake of Otx2 homeoprotein into the enwrapped PV-cells required for their maintenance (27, 40, 41) (Fig. S3).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [27] Sugiyama, 2008, Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity, Cell source
Not checked in the free run.
- cites [40] Miyata, 2012, Persistent cortical plasticity by upregulation of chondroitin 6-sulfation, Nat Neurosci source
Not checked in the free run.
- cites [41] Beurdeley, 2012, Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex, J Neurosci source
Not checked in the free run.
- Premisecitation
The classical loss of input from an eye briefly deprived of vision in the binocular zone of primary visual cortex is typically constrained before P50.
“The classical loss of input from an eye briefly deprived of vision in the binocular zone of primary visual cortex is typically constrained before P50 (reviewed in ref. (46, 47)) (Fig 4A).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Two primary PNN components, chondroitin sulfate and hyaluronan, are sensitive to excessive free radicals.
“Two of the primary PNN components, chondroitin sulfate and hyaluronan, are sensitive to excessive free radicals (52)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52] Rees, 2004, Hypochlorite and superoxide radicals can act synergistically to induce fragmentation of hyaluronan and chondroitin sulphates, Biochem J source
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- Interpretationreasoning
Redox dysregulation in schizophrenia may act in part by transiently prolonging or reopening critical periods of developmental plasticity.
“Paradoxically, redox dysregulation in schizophrenia may then act in part by transiently prolonging or reopening critical periods of developmental plasticity.”
Quote in the paperSubstantial claim- Rests on an assumption: The prolonged plasticity observed in PV-Gclc KO mice is not mediated by an unknown consequence of Gclc deletion unrelated to redox dysregulation.
- Premisecitation
Altered PNNs have been found in the human post mortem amygdala, entorhinal and prefrontal cortices of patients.
“Altered PNNs have been found in the human post mortem amygdala, entorhinal and prefrontal cortices of patients (65–67)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [65] Berretta, 2012, Extracellular matrix abnormalities in schizophrenia, Neuropharmacology source
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- cites [66] Pantazopoulos, 2010, Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia, Arch Gen Psychiatry source
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- cites [67] Mauney, 2013, Developmental pattern of perineuronal nets in the human prefrontal cortex and their deficit in schizophrenia, Biol Psychiatry source
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- Interpretationcitation
Inability to engage downstream molecular pathways by Otx2 within the PV cell would retain a juvenile plastic state.
“Subsequent inability to engage downstream molecular pathways by Otx2 within the PV-cell would retain a juvenile plastic state (41).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Beurdeley, 2012, Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex, J Neurosci source
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- Premisecitation
GABA-related functional deficits are seen even in the visual cortex of schizophrenia patients.
“and GABA-related functional deficits are seen even in their visual cortex (68–71).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [68] Rokem, 2011, Broader visual orientation tuning in patients with schizophrenia, Front Hum Neurosci source
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- cites [69] Yoon, 2010, GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression, J Neurosci source
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- cites [70] Hashimoto, 2008, Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia, Am J Psychiatry source
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- cites [71] Kim, 2005, Dysfunction of early-stage visual processing in schizophrenia: Harmonic analysis, Schizophr Res source
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- Interpretationreasoning
Cell-autonomous redox dysregulation within PV cells is the primary contributor to the reduction of PNNs observed across mouse models and human patients sharing global redox dysregulation.
“Our study suggests that cell-autonomous redox dysregulation within PV-cells is the primary contributor to a reduction of PNNs observed across mouse models and human patients sharing global redox dysregulation.”
Quote in the paperSubstantial claim- Rests on an assumption: The prolonged plasticity observed in PV-Gclc KO mice is not mediated by an unknown consequence of Gclc deletion unrelated to redox dysregulation.
- Premisecitation
A recent study by the authors revealed a protective function of PNNs as a redox sensor.
“Our recent study revealed a protective function of these PNNs as a redox sensor (53).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Cabungcal, 2013, Perineuronal nets protect fast-spiking interneurons against oxidative stress, Proc Natl Acad Sci U S A source
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- Premisecitation
Individuals at high risk show greater cognitive gains relative to adults with chronic schizophrenia in response to computer-based cognitive training.
“Individuals at high risk show greater cognitive gains relative to adults with chronic schizophrenia in response to computer-based cognitive training (60).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [60] Rauchensteiner, 2011, Test-performance after cognitive training in persons at risk mental state of schizophrenia and patients with schizophrenia, Psychiatry Res source
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- Interpretationreasoning
Mis-timed developmental trajectories of brain plasticity may contribute in part to the etiology of mental illnesses involving oxidative stress, such as schizophrenia.
“Mis-timed developmental trajectories of brain plasticity may therefore contribute in part to the etiology of mental illnesses involving oxidative stress, such as schizophrenia (2, 3, 18).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [2] Insel, 2010, Rethinking schizophrenia, Nature source
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- cites [3] Do, 2009, Redox dysregulation, neurodevelopment, and schizophrenia, Curr Opin Neurobiol source
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- cites [18] Cabungcal, 2014, Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia, Neuron source
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- Interpretationcitation
The prolonged plasticity reflects a redox-sensitive failure to maintain PV cells with fully enwrapped PNNs, which normally balance plasticity and stability of cortical circuits across development.
“This reflects a redox-sensitive failure to maintain PV-cells with fully enwrapped PNNs, which normally balance plasticity and stability of cortical circuits across development in a twofold manner (38, 39).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
High metabolic requirements of fast-spiking PV interneurons may readily generate reactive oxygen species when antioxidant systems are impaired, leading to breakdown of PNNs.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [23] Behrens, 2007, Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase, Science source
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- cites [53] Cabungcal, 2013, Perineuronal nets protect fast-spiking interneurons against oxidative stress, Proc Natl Acad Sci U S A source
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- Premisecitation
In chronic schizophrenia patients, deficits in visual cortex and long-term potentiation-like plasticity are reported when probed by transcranial direct current stimulation.
“In chronic schizophrenia patients, deficits in visual cortex and long-term potentiation-like plasticity are reported when probed by transcranial direct current stimulation (55–58).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [55] Daskalakis, 2008, Dysfunctional neural plasticity in patients with schizophrenia, Arch Gen Psychiatry source
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- cites [56] McClintock, 2011, Transcranial magnetic stimulation: A neuroscientific probe of cortical function in schizophrenia, Biol Psychiatry source
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- cites [57] Mears, 2012, Electrophysiological assessment of auditory stimulus-specific plasticity in schizophrenia, Biol Psychiatry source
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- cites [58] Cavus, 2012, Impaired visual cortical plasticity in schizophrenia, Biol Psychiatry source
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- Interpretationnone given
The relatively late timing of Gclc deletion overlaps with the usual condensation of PNN components into tight nets around PV cells.
“the relatively late timing of Gclc deletion here overlaps with their usual condensation into tight nets around PV-cells.”
Quote in the paperSubstantial claim - Premisecitation
Intact PNNs may structurally limit robust synaptic plasticity directly upon PV cells.
“First, intact PNNs may structurally limit the robust synaptic plasticity directly upon PV-cells (48–50).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [48] Yazaki-Sugiyama, 2009, Bidirectional plasticity in fast-spiking GABA circuits by visual experience, Nature source
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- cites [49] Kuhlman, 2013, A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex, Nature source
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- cites [50] Aton, 2013, Visual experience and subsequent sleep induce sequential plastic changes in putative inhibitory and excitatory cortical neurons, Proc Natl Acad Sci U S A source
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- Interpretationcitation
Pathophysiological changes are consistent with dematuration or removal of brakes on plasticity.
“Pathophysiological changes (1–3) are consistent with ‘dematuration’ or a removal of ‘brakes’ on plasticity (72, 73).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [72] Bavelier, 2010, Removing brakes on adult brain plasticity: From molecular to behavioral interventions, J Neurosci source
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- cites [73] Hagihara, 2014, Transcriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia, Mol Brain source
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- Interpretationcitation
All brakes to date converge on PV-cell function as a hub of vulnerability.
“Curiously, all brakes to date converge on PV-cell function as a hub of vulnerability (77).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [77] Takesian, 2013, Balancing plasticity/stability across brain development, Prog Brain Res source
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- May combine two claims. 13
- Classified as probably not a substantial claim. 14
May combine two claims.
Findingown dataIn CamK2-Gclc KO mice, massive activation of microglia and neurodegeneration were observed.
“Consistent with a more widespread redox dysregulation across the pyramidal cell population, a massive activation of microglia (Figure 3C) and neurodegeneration (Supplemental Figure S2) was observed”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn CamK2-Gclc KO mice, no extended plasticity was seen, similar to typical adult WT mice.
“Moreover, in CamK2-Gclc KO mice, carrying a more severe redox dysregulation restricted to pyramidal cells, no extended plasticity was seen as in typical adult WT mice (Figure 4D,E; CBI = 0.69 and 0.67, respectively; p>0.8).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Premisenone givenOxidative stress and specific impairment of peri-somatic GABA circuits are hallmarks of the schizophrenic brain and its animal models.
“Oxidative stress and the specific impairment of peri-somatic GABA circuits are hallmarks of the schizophrenic brain and its animal models.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationReduced antioxidant enzymes have been reported in patients with schizophrenia.
“Reduced antioxidant enzymes are reported in schizophrenic patients (4–8)”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [4] Do, 2000, Schizophrenia: Glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo, Eur J Neurosci source
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- cites [5] Andreazza, 2008, Oxidative stress markers in bipolar disorder: A meta-analysis, J Affect Disord source
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- cites [6] Yao, 2011, Antioxidants, redox signaling, and pathophysiology in schizophrenia: An integrative view, Antioxid Redox Signal source
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- cites [7] Wang, 2009, Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia, Bipolar Disord source
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- cites [8] Gawryluk, 2011, Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders, Int J Neuropsychopharmacol source
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Classified as probably not a substantial claim. May combine two claims.
PremisecitationSchizophrenia is increasingly viewed as a neurodevelopmental disorder involving brain circuit alterations, including dysfunction of parvalbumin-positive fast-spiking GABA neurons.
“Schizophrenia is increasingly recognized as a neurodevelopmental disorder that involves alterations in brain circuits, including dysfunction of parvalbumin (PV)-positive, fast-spiking GABA neurons (1, 2).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningProlonged developmental plasticity may offer a therapeutic opportunity for cognitive interventions targeting brain plasticity in schizophrenia.
“Such prolonged developmental plasticity may in turn offer a therapeutic opportunity for cognitive interventions targeting brain plasticity in schizophrenia.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMultiple genetic and external factors collectively lead to redox dysregulation.
“several divergent genetic (e.g. Gclc, Gclm, Disc1, PRODH, G72, NRG1) (9–17) or external factors (e.g. stress, social isolation, ketamine, neonatal ventral hippocampal lesion) (18–24) collectively lead to redox dysregulation.”
Quote in the paperNot a substantial claim0 of 10 sources checked- cites [9] Gysin, 2007, Impaired glutathione synthesis in schizophrenia: Convergent genetic and functional evidence, Proc Natl Acad Sci U S A source
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- cites [10] Tosic, 2006, Schizophrenia and oxidative stress: Glutamate cysteine ligase modifier as a susceptibility gene, Am J Hum Genet source
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- cites [11] Park, 2010, Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin, Proc Natl Acad Sci U S A source
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- cites [12] Gokhale, 2012, Quantitative proteomic and genetic analyses of the schizophrenia susceptibility factor dysbindin identify novel roles of the biogenesis of lysosome-related organelles complex 1, J Neurosci source
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- cites [13] Goldshmit, 2001, Neuregulin rescues PC12-ErbB4 cells from cell death induced by H(2)O(2). Regulation of reactive oxygen species levels by phosphatidylinositol 3-kinase, J Biol Chem source
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- cites [14] Otte, 2011, N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice, Neuropsychopharmacology source
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- cites [15] Krishnan, 2008, Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress, Free Radic Biol Med source
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- cites [16] Steullet, 2010, Redox dysregulation affects the ventral but not dorsal hippocampus: Impairment of parvalbumin neurons, gamma oscillations, and related behaviors, J Neurosci source
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- cites [17] Kulak, 2013, Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: Insights from animal models, Antioxid Redox Signal source
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- cites [18] Cabungcal, 2014, Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia, Neuron source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe study cannot rule out a mild non-cell autonomous increase of oxidative stress below the detection threshold of the 8-oxo-dG staining.
“Note that we cannot rule out the possibility of mild non-cell autonomous increase of oxidative stress below detection of our 8-oxo-dG staining threshold set to capture only those cells with enhanced oxidative stress beyond the basal levels of physiological stress.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationPerineuronal nets normally enwrap mature fast-spiking cells and limit adult plasticity.
“which normally enwrap mature fast-spiking cells to limit adult plasticity”
- Also stated in: § Redox dysregulation decreases perineuronal nets enwrapping PV-cells · plain
“Enzymatic removal of PNNs can reopen plasticity in adulthood (38, 39).”
Quote in the paperSubstantial claim0 of 2 sources checked- Also stated in: § Redox dysregulation decreases perineuronal nets enwrapping PV-cells · plain
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe major endogenous source of Otx2 has been identified as the choroid plexus, which lines ventricles commonly enlarged in schizophrenia.
“Notably, the major endogenous source of this Otx2 has recently been identified as the choroid plexus (51), which lines the ventricles that are commonly found to be enlarged in schizophrenia.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [51] Spatazza, 2013, Choroid-plexus-derived otx2 homeoprotein constrains adult cortical plasticity, Cell Rep source
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Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationAn excessively plastic status may precede the progressive degenerative process as in other brain disorders.
“An excessively plastic status may precede the progressive degenerative process as in other brain disorders (29, 54).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningPNN loss might allow diffusion of excessive reactive oxygen species outside the PV cell, which might signal microglial cells.
“PNN loss might allow the diffusion of excessive reactive oxygen species outside the PV-cell, which might signal microglial cells.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMicroglia have been implicated as active participants in brain plasticity.
“Microglia have recently been implicated as active participants in brain plasticity per se (42–45).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [42] Tremblay, 2010, Microglial interactions with synapses are modulated by visual experience, PLoS Biol source
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- cites [43] Paolicelli, 2011, Synaptic pruning by microglia is necessary for normal brain development, Science source
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- cites [44] Schafer, 2012, Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner, Neuron source
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- cites [45] Tremblay, 2011, A role for microglia in synaptic plasticity?, Commun Integr Biol source
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May combine two claims.
InterpretationreasoningThe contribution of microglial response to cortical plasticity may be more subtle than expected or reflect an optimal range of activation.
“Given the inverse relationship of microglial activation and the level of cortical plasticity in adult PV- and CamK2-Gclc KO mice, the contribution of microglial response to cortical plasticity may be more subtle than expected or reflect an optimal range of activation.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe results reveal a prolonged period of brain plasticity or failure to stabilize cortical circuits in young adult animals under PV-cell-specific glutathione dysregulation in vivo.
“Our results reveal a prolonged period of brain plasticity – or a failure to stabilize cortical circuits - in young adult animals under conditions of PV-cell specific glutathione dysregulation in vivo.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationcitationProlonged developmental plasticity may provide a diagnostic opportunity for cognitive interventions targeting brain plasticity in the prodromal stage.
“Prolonged developmental plasticity may then provide a diagnostic opportunity for cognitive interventions targeting brain plasticity in the prodromal stage (62–64).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [62] Vinogradov, 2012, de Villers-Sidani E, Cognitive training for impaired neural systems in neuropsychiatric illness. Neuropsychopharmacology
Not checked in the free run.
- cites [63] Kaneko, 2012, Cognitive remediation in schizophrenia, Clin Psychopharmacol Neurosci source
Not checked in the free run.
- cites [64] Fisher, 2013, Cognitive interventions targeting brain plasticity in the prodromal and early phases of schizophrenia, Annu Rev Clin Psychol source
Not checked in the free run.
May combine two claims.
Interpretationown dataPV cells did not die in PV-Gclc KO mice but were rather impaired.
“suggesting that PV-cells did not die in PV-Gclc KO mice but were rather impaired (Supplemental Figure S2).”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductreasoningThe current study was limited before and after the age range P54-63, either by premature death of PV-Gclc KO mice by P80 or insufficient deletion of Gclc at younger stages.
“Unfortunately, the current study was limited before and after the age range we studied (P54–63), either by premature death of PV-Gclc KO mice by P80 (as PV is also expressed in muscle) or insufficient deletion of the Gclc gene at younger stages.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationAn earlier window may correct the plasticity phenotype.
“suggesting an earlier window may correct the plasticity phenotype (18).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Cabungcal, 2014, Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia, Neuron source
Not checked in the free run.
May combine two claims.
PremisecitationFirst onset patients do not differ significantly from healthy controls in plasticity, with a trend toward increased plasticity.
“First onset patients instead do not differ significantly from healthy controls with a trend toward increased plasticity (59).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [59] Hasan, 2011, Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation, Behav Brain Res source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningThis convergence may offer novel strategies or drug targets for correcting aberrant brain plasticity in mental illness.
“This may offer novel strategies or drug targets, in addition to antioxidants (18, 25) or Otx2 up-regulation (41, 51), for correcting aberrant brain plasticity in mental illness.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [18] Cabungcal, 2014, Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia, Neuron source
Not checked in the free run.
- cites [25] Cabungcal, 2013, Early-life insults impair parvalbumin interneurons via oxidative stress: Reversal by N-acetylcysteine, Biol Psychiatry source
Not checked in the free run.
- cites [41] Beurdeley, 2012, Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex, J Neurosci source
Not checked in the free run.
- cites [51] Spatazza, 2013, Choroid-plexus-derived otx2 homeoprotein constrains adult cortical plasticity, Cell Rep source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSeveral molecular brakes relevant to schizophrenia, other than PNNs, limit critical period plasticity, including myelin signaling through NgR-PirB and dampened nicotinic receptor signaling by Lynx1.
“Several molecular brakes of relevance to schizophrenia (other than PNNs) have been identified to limit critical period plasticity, including myelin signaling through a NgR-PirB complex (2, 74, 75) or dampened nicotinic receptor signaling by Lynx1 (29, 76).”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [2] Insel, 2010, Rethinking schizophrenia, Nature source
Not checked in the free run.
- cites [74] McGee, 2005, Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor, Science source
Not checked in the free run.
- cites [75] Syken, 2006, PirB restricts ocular-dominance plasticity in visual cortex, Science source
Not checked in the free run.
- cites [29] Morishita, 2010, Lynx1, a cholinergic brake, limits plasticity in adult visual cortex, Science source
Not checked in the free run.
- cites [76] Stark, 2008, Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model, Nat Genet source
Not checked in the free run.
The paper relies on this without support.
The prolonged plasticity observed in PV-Gclc KO mice is not mediated by an unknown consequence of Gclc deletion unrelated to redox dysregulation.
“Also, we cannot fully rule out the possibility that the prolonged plasticity in these mice is mediated by an as yet unknown consequence of Gclc deletion not directly related to redox dysregulation.”
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?
Redox dysregulation disrupts critical period plasticity in the developing cortex of mice.
“and, consequently, also disrupts critical period plasticity in the developing cortex of mice 84 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [84]
PNNs may protect PV cells from oxidative stress, and thus serve as a 'safety net' to support the rapid firing properties of PV cells.
“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 Morishita et al., 2015
Extracellular matrix components, including perineuronal nets, are critical regulators of synaptic plasticity.
“Several studies suggest that ECM components, including PNNs, are critical regulators of synaptic plasticity (Do et al, 2015;Miyata et al, 2012;Morishita et al, 2015).”
From Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia (2016) · cites this paper as Morishita et al, 2015
Perineuronal nets appear to be both protective against and altered by high levels of oxidative stress.
“Finally, PNNs appear to be both protective against and altered by high levels of oxidative stress (Cabungcal et al, 2013a;Do et al, 2015;Morishita et al, 2015).”
From Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia (2016) · cites this paper as Morishita et al, 2015
PVIs are vulnerable to redox dysregulation/oxidative stress.
“Indeed, PVIs are vulnerable to redox dysregulation/oxidative stress.37, 38, 39, 40”
From Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia (2017) · cites this paper as [40]
Cell-autonomous redox dysregulation from deleting Gclc only in PV-cells is enough to prolong critical-period plasticity.
“Direct cell autonomous redox dysregulation by deletion of the primary antioxidant (glutathione) synthetic enzyme (Gclc) only within PV-cells is sufficient to prolong critical period plasticity (Morishita et al., 2015).”
From Clock Genes Control Cortical Critical Period Timing (2015) · cites this paper as Morishita et al., 2015
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Germline recombination by conditional gene targeting with Parvalbumin-Cre lines
Kobayashi, Y., & Hensch, T. K. (2013) · Frontiers in Neural Circuits · doi:10.3389/fncir.2013.00168 · Cited by 30 · see citing works
Self-citationHijacking Hebb: Noninvasive Methods to Probe Plasticity in Psychiatric Disease
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Flagged first, then by citations
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Cited by
Sorted by citations
The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function
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Critical period regulation across multiple timescales
Reh, R. K., Dias, B. G., Nelson, C. A., Kaufer, D., Werker, J. F., Kolb, B., Levine, J. D., & Hensch, T. K. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820836117 · Cited by 492 · see citing works
Self-citationDevelopmental timing and critical windows for the treatment of psychiatric disorders
Marín, O. (2016) · Nature Medicine · doi:10.1038/nm.4225 · Cited by 374 · see citing works
Steullet, P., Cabungcal, J.-H., Coyle, J., Didriksen, M., Gill, K., Grace, A. A., Hensch, T. K., LaMantia, A.-S., Lindemann, L., Maynard, T. M., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.47 · Cited by 360 · see citing works
Self-citationLinking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis
Hardingham, G. E., & Do, K. Q. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2015.19 · Cited by 304 · see citing works
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The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders
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Do, K. Q., Cuenod, M., & Hensch, T. K. (2015) · Schizophrenia Bulletin · doi:10.1093/schbul/sbv065 · Cited by 158 · see citing works
Self-citationClock Genes Control Cortical Critical Period Timing
Kobayashi, Y., Ye, Z., & Hensch, T. K. (2015) · Neuron · doi:10.1016/j.neuron.2015.02.036 · Cited by 99 · see citing works
Self-citationOtx2-PNN interaction to regulate cortical plasticity
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Self-citationGenome-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 · see citing works
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- Authors
- Morishita, H., Cabungcal, J.-H., Chen, Y., Do, K. Q., & Hensch, T. K.
- Affiliations
- Boston Children's Hospital (US)
- Centre Hospitalier Universitaire Vaudois (CH)
- University of Colorado Denver (US)
- Corresponding author
- Hensch, Takao K.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 78
- Issue
- 6
- Pages
- 396-402
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4514575
- OpenAlex
- W2017270601
- Cited by
- 92
- References
- 75
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 9 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 8 · 2019: 9 · 2018: 9 · 2017: 11 · 2016: 11 · 2015: 9
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Institutes of Health (1DP1OD003699, 1P50MH094271)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- redox dysregulation, oxidative stress, fast-spiking interneurons, parvalbumin, cortical plasticity, critical period, perineuronal nets, schizophrenia, GABAergic circuits, visual cortex development
- MeSH terms
- Adaptation, Physiological, Animals, Extracellular Matrix, Glutamate-Cysteine Ligase, Interneurons, Mice, Inbred C57BL, Neuronal Plasticity, Oxidation-Reduction, Parvalbumins, Sensory Deprivation, Visual Cortex, Microglia, Oxidative Stress, GABAergic Neurons
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
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 ›
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