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Cited by 152Schizophrenia research and treatmentNeuroscience and Neuropharmacology ResearchTryptophan and brain disorders

Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia

Open access
Berretta, Sabina, Pantazopoulos, Harry, Markota, Matej, Brown, Christopher, Batzianouli, Eleni T.·2015·Schizophrenia Research
DOI 10.1016/j.schres.2014.12.040PMC PMC4504843
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Abstract

Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia. In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex. The formation of these specialized extracellular matrix (ECM) aggregates during postnatal development, their functions, and association with distinct populations of GABAergic interneurons, bear great relevance to the pathophysiology of schizophrenia. PNNs gradually mature in an experience-dependent manner during late stages of postnatal development, overlapping with the prodromal period/age of onset of schizophrenia. Throughout adulthood, PNNs regulate neuronal properties, including synaptic remodeling, cell membrane compartmentalization and subsequent regulation of glutamate receptors and calcium channels, and susceptibility to oxidative stress. With the present paper, we discuss evidence for PNN abnormalities in schizophrenia, the potential functional impact of such abnormalities on inhibitory circuits and, in turn, cognitive and emotion processing. We integrate these considerations with results from recent genetic studies showing genetic susceptibility for schizophrenia associated with genes encoding for PNN components, matrix-regulating molecules and immune system factors. Notably, the composition of PNNs is regulated dynamically in response to factors such as fear, reward, stress, and immune response. This regulation occurs through families of matrix metalloproteinases that cleave ECM components, altering their functions and affecting plasticity. Several metalloproteinases have been proposed as vulnerability factors for schizophrenia. We speculate that the physiological process of PNN remodeling may be disrupted in schizophrenia as a result of interactions between matrix remodeling processes and immune system dysregulation. In turn, these mechanisms may contribute to the dysfunction of GABAergic neurons.

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Crossref · 10.1016/j.schres.2014.12.040

Cites

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Claims the paper makes

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  • Findingcitation

    Our group has shown marked decreases of PNNs in several brain regions of subjects diagnosed with schizophrenia.

    “Our group has shown marked decreases of PNNs in several brain regions of subjects diagnosed with SZ (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”
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    • cites Pantazopolous et al., 2014

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    • cites Pantazopoulos et al., 2010 source

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  • Findingcitation

    PNN decreases have been detected in the amygdala, entorhinal cortex, and prefrontal cortex of subjects with schizophrenia.

    “In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex.”
    • Also stated in: § 2. PERINEURONAL NET ABNORMALITIES IN SCHIZOPHRENIA · plain
      “Lower numbers of WFA-labeled PNNs were detected in the amygdala, entorhinal and prefrontal cortex (Mauney et al., 2013; Pantazopoulos et al., 2010).”
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  • Findingcitation

    The distribution of WFA-labeled PNN reductions in schizophrenia matches the normal distribution of WFA-labeled PNNs and GABAergic interneurons expressing parvalbumin.

    “The distribution of these changes matches closely not only the normal distribution of WFA-labeled PNNs, but also that of GABAergic interneurons expressing PVB (Pantazopoulos et al., 2010).”
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    • cites Pantazopoulos et al., 2010 source

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  • Findingown data

    About a third of WFA-labeled PNNs in the human amygdala ensheath other neuronal populations, including interneurons expressing somatostatin.

    “This result confirms the association of WFA-labeled PNNs with PVB-positive neurons, yet indicates that about a third of these PNNs ensheaths other neuronal populations. Among these are interneurons expressing somatostatin (Fig. 4; unpublished data), a particular interesting neuronal population in light of their expression of the voltage-gated potassium channel subunit Kv3, which may confer them”
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  • Findingcitation

    In the human amygdala, only approximately 54% of aggrecan-labeled PNNs were co-labeled with WFA.

    “Our results show that only approximately 54% of aggrecan-labeled PNNs were co-labeled with WFA.”
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    Findingcitation

    Numbers of parvalbumin-expressing neurons were normal in the amygdala and entorhinal cortex, and densities of WFA-labeled PNNs were unchanged in the central nucleus of the amygdala and visual cortex of subjects with schizophrenia.

    “Notably, numbers of these neurons were normal in the amygdala and entorhinal cortex, and densities of WFA-labeled PNNs were unchanged in the central nucleus of the amygdala and visual cortex of subjects with SZ (Mauney et al., 2013; Pantazopoulos et al., 2010)(Fig. 3, unpublished data).”
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    Findingown data

    PNNs labeled with the CS-6 sulfation antibody 3B3 were substantially more numerous and displayed a broader distribution in the human amygdala than WFA-labeled PNNs.

    “PNNs labeled with the CS-6 sulfation antibody 3B3 were substantially more numerous, and displayed a broader distribution in the human amygdala with respect to WFA-labeled PNNs.”
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    Findingcitation

    Within each brain structure examined, WFA-labeled PNN reductions in schizophrenia were selective for distinct subregions: the lateral nucleus of the amygdala, superficial layers of the entorhinal cortex, and layers III and V of the prefrontal cortex.

    “Within each brain structure examined, WFA-labeled PNN reductions were selective for distinct subregions, i.e. the lateral nucleus of the amygdala, superficial layers of the entorhinal cortex and layers III and V of the prefrontal cortex.”
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    Findingcitation

    In the human amygdala, 68% of WFA-labeled PNNs envelop parvalbumin-positive neurons, a small percentage of which also express calbindin.

    “In the human amygdala, 68% of WFA-labeled PNNs envelop PVB-positive neurons, a small percentage of which also express calbindin (Pantazopoulos et al., 2006).”
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    • cites Pantazopoulos et al., 2006 source

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    Findingown data

    PNNs containing versican (v0/v1 isoform) were detected selectively in the central nucleus of the human amygdala, but not in other amygdala nuclei, and represented a distinct population from WFA-containing PNNs.

    “Furthermore, PNNs containing versican (v0/v1 isoform) were detected selectively in the central nucleus (Fig. 3), but not in other amygdala nuclei, and represented a clearly distinct population with respect to those containing WFA (unpublished observations).”
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    Findingcitation

    In the lateral nucleus of the human amygdala, 49% of 3B3-IR PNNs are co-labeled with WFA; this percentage decreases drastically in other amygdala nuclei where the large majority of PNNs was 3B3-positive but WFA-negative.

    “In the lateral nucleus, 49% of 3B3-IR PNNs are co-labeled with WFA; this percentage decreases drastically in the other amygdala nuclei where the large majority of PNNs was 3B3-positive but WFA-negative.”
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    • cites Pantazopolous et al., 2014

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    Findingown data

    Decreases of aggrecan-immunoreactive PNNs in schizophrenia were selective for the lateral nucleus of the amygdala, similar to previous observations using WFA.

    “Decreases of aggrecan-immunoreactive PNNs were selective for the lateral nucleus of the amygdala, similar to previous observations using WFA.”
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    • cites Pantazopolous et al., 2014

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    Findingcitation

    In the human prefrontal cortex, numbers of PNNs gradually increase from childhood through early adulthood, consistent with their role in regulating prefrontal cortex circuit refinement.

    “Consistently, in the human PFC, numbers of PNNs gradually increase from childhood through early adulthood, consistent with their role in regulating human prefrontal cortex circuit refinement (Mauney et al., 2013).”
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    Premisenone given

    Matrix metalloproteinases cleave ECM components, altering their functions and affecting plasticity.

    “This regulation occurs through families of matrix metalloproteinases that cleave ECM components, altering their functions and affecting plasticity.”
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    Premisecitation

    PNNs are heterogeneous in composition, with only a subgroup labeled by WFA.

    “Immunolabeling using antibodies against CSPG protein cores or sulfation patterns shows that PNNs are heterogeneous in composition, with only a subgroup labeled by WFA.”
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    • cites Ajmo et al., 2008

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    Interpretationreasoning

    3B3-labeled PNNs show clear interneuron-like morphology, suggesting that a large population of interneurons in the amygdala is associated with 3B3-labeled PNNs.

    “Like WFA-labeled PNNs, 3B3-labeled PNNs show clear interneuron-like morphology, suggesting that a large population of interneurons in the amygdala is associated with 3B3-labeled PNNs (see also below).”
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    Premisecitation

    PNNs are specialized aggregates of extracellular matrix molecules surrounding the somata, dendrites, and proximal axon segment of distinct neuronal populations.

    “Perineuronal nets (PNNs), first described by Camillo Golgi in 1898, are specialized aggregates of extracellular matrix (ECM) molecules surrounding the somata, dendrites and proximal axon segment of distinct neuronal populations (Fig. 1) (Brauer et al., 1993; Celio et al., 1998; Golgi, 1898; Kwok et al., 2011; Seeger et al., 1994; Spreafico et al., 1999; Vitellaro-Zuccarello et al., 1998).”
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    Premisenone given

    PNN composition is dynamically regulated in response to fear, reward, stress, and immune response.

    “Notably, the composition of PNNs is regulated dynamically in response to factors such as fear, reward, stress, and immune response.”
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    Premisenone given

    Several metalloproteinases have been proposed as vulnerability factors for schizophrenia.

    “Several metalloproteinases have been proposed as vulnerability factors for schizophrenia.”
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    Premisecitation

    Reelin and semaphorin 3A are involved in the pathophysiology of schizophrenia, although not directly as PNN components.

    “Importantly, other PNN elements, namely Reelin and semaphorin 3A, have been shown to be involved in the pathophysiology of SZ, although not directly as PNN components (Abdolmaleky et al., 2005a; Carulli et al.,”
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    Premisecitation

    In the amygdala of rhesus monkey, the overwhelming majority of WFA-positive PNNs ensheath neurons expressing glutamic acid decarboxylase, with many also expressing parvalbumin and/or calbindin.

    “As an example, in the amygdala of rhesus monkey, the overwhelming majority of WFA-positive PNNs ensheath neurons expressing glutamic acid decarboxylase (GAD), a typical marker for GABAergic neurons, with many of these neurons also expressing PVB and/or calbindin (Hartig et al., 1995).”
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    Premisecitation

    CSPGs are organizers of the ECM and are highly represented in PNNs, with aggrecan, neurocan, brevican, versican, and phosphacan among the most abundant.

    “CSPGs, the organizers of the ECM, are highly represented in PNNs, with aggrecan, neurocan, brevican, versican and phosphacan among the most abundant (Deepa et al., 2006; Giamanco and Matthews, 2012; Yamaguchi, 2000).”
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    Interpretationown data

    PNN abnormalities in schizophrenia are restricted in their distribution to specific cortical layers and amygdala nuclei, suggesting specialized mechanisms affecting distinct neuronal populations.

    “Yet, they are restricted in their distribution to specific cortical layers and amygdala nuclei, suggesting specialized mechanisms affecting distinct neuronal populations.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    Such disruption may contribute to increased amygdala activity, consistent with observations in schizophrenia subjects tonically and during the processing of emotional stimuli.

    “Such disruption may contribute to increased amygdala activity, consistent with observation in SZ subjects tonically and during the processing of emotional stimuli (Holt et al., 2006; Rauch et al., 2010; Suslow et al., 2013; Taylor et al., 2005).”
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    Interpretationown data

    Reductions of WFA-labeled PNNs in schizophrenia do not simply reflect loss of parvalbumin-expressing neurons, and impact selective populations of these neurons in a region-selective manner.

    “Together, these findings suggest that reductions of WFA-labeled PNNs in SZ do not simply reflect loss of PVB-expressing neurons, and impact selective populations of these neurons in a region-selective manner.”
    Quote in the paperSubstantial claim

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    Premisecitation

    PNNs restrict the lateral diffusion of AMPA receptors and thus allow synaptic desensitization.

    “This process, proposed to represent a fundamental mechanism for the maintenance of synaptic receptor pools, has been shown to controlled by PNNs, which restricted the lateral diffusion of AMPA receptors and thus allow synaptic desensitization (Frischknecht and Gundelfinger, 2012; Frischknecht et al., 2009; Heine et al., 2008).”
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    Interpretationreasoning

    PNN disruption in schizophrenia may result in synaptic dysregulation and altered firing properties of PNN-bearing neurons.

    “The considerations above highlight the effects of PNNs on synaptic functions and support the idea that PNN disruption in SZ may result in synaptic dysregulation and altered firing properties of PNN-bearing neurons.”
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    Premisecitation

    In a rodent model, PNN enzymatic degradation in the ventral hippocampus resulted in increased activity of pyramidal neurons, postulated to result from disruption of GABAergic neuronal activity following PNN loss.

    “In this study, PNN enzymatic degradation in the ventral hippocampus resulted in increased activity of pyramidal neurons, postulated to result from disruption of GABAergic neuronal activity following PNN loss (Shah and Lodge, 2013).”
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    • cites Shah and Lodge, 2013 source

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    Study design and conductcitation

    PNN abnormalities in schizophrenia are large in magnitude, robust to confounding factors, and shared by several brain regions involved in schizophrenia.

    “These abnormalities are large in magnitude, robust to confounding factors and shared by several brain regions involved in SZ (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”
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    Interpretationcitation

    Only one-third (30%) of WFA-positive PNNs also express aggrecan, raising the possibility that neuronal populations affected by WFA- and aggrecan-positive PNN loss only partially overlap.

    “However, only one-third (30%) of WFA-positive PNNs also expresses aggrecan, raising the possibility that neuronal populations affected by WFA- and aggrecan-positive PNN loss only partially overlap.”
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    Premisecitation

    Localized enzymatic CSPG digestion in adult animals caused a reversal to a juvenile form of fear conditioning, one that can be fully erased by extinction.

    “Localized enzymatic CSPG digestion in adult animals caused a reversal to a juvenile form of fear conditioning, one that can be fully erased by extinction (Gogolla et al., 2009; Kim and Richardson, 2007).”
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    Study design and conductcitation

    In subjects with schizophrenia, decreases of PNNs in multiple brain regions were robust to confounding variables, including exposure to pharmacological agents, and did not correlate with age at onset of the disease or duration of illness.

    “In subjects with SZ, decreases of PNNs in multiple brain regions were robust to confounding variables, including exposure to pharmacological agents, and did not correlate with age at onset of the disease or duration of illness (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”
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    Premisecitation

    CSPG/PNN degradation in the amygdala in combination with extinction training resulted in erasure of drug-related memories, facilitated extinction of drug-seeking behavior, and prevented spontaneous recovery and drug-induced reinstatement of drug-seeking behavior.

    “In their experiments, CSPG/PNN degradation in the amygdala in combination with extinction training resulted in erasure of drug (cocaine, morphine)-related memories, facilitated the extinction of drug-seeking behavior and prevented the spontaneous recovery and drug-induced reinstatement of drug-seeking behavior (Xue et al., 2014).”
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    Premisecitation

    Glial cells are a major source of CSPGs and critically contribute to PNN formation and maintenance.

    “Glial cells are a main source of chondroitin sulfate proteoglycans (abbreviated here as CSPGs), and have been shown to critically contribute to the formation and maintenance of PNNs (Faissner et al., 2010; John et al., 2006; Klausmeyer et al., 2011; Wiese et al., 2012).”
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    Interpretationcitation

    PNN abnormalities in schizophrenia may be inherent to this disorder and, perhaps, present at its onset.

    “These observations are consistent with the idea that PNN abnormalities in SZ may be inherent to this disorder and, perhaps, present at its onset.”
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    Interpretationcitation

    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.

    “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).”
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    Premisecitation

    The implementation of the adult form of ECM coincides with the closure of critical periods of postnatal development and culminates with the maturation of PNNs and PNN-like perisynaptic ECM aggregates.

    “The implementation of this adult form of ECM coincides with the closure of critical periods of postnatal development, during which neuronal circuits are shaped by experience, and culminates with the maturation of PNNs and PNN-like perisynaptic ECM aggregates (Balmer et al., 2009; Gogolla et al., 2009; Gundelfinger et al., 2010; McRae et al., 2007; Nowicka et al., 2009; Pizzorusso et al., 2002;”
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    Premisecitation

    PNN gradual maturation around somata and dendrites stabilizes successful synapses, restricting plasticity, regulating synaptogenesis, and maintaining mature forms of learning.

    “PNN gradual maturation around somata and dendrites stabilizes successful synapses, restricting plasticity, regulating synaptogenesis and maintaining mature forms of learning (Bukalo et al., 2001; Carulli et al., 2013b; Dityatev et al., 2007; Faissner et al., 2010; Gundelfinger et al., 2010; McRae and Porter, 2012; Pyka et al., 2011).”
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    Interpretationcitation

    PNN abnormalities in schizophrenia may profoundly impact emotion processing and plasticity.

    “Together, this evidence suggests that PNN abnormalities in SZ may profoundly impact emotion processing and plasticity.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Reduced CSPG availability, possibly partly genetic, may cause failure of PNN formation during late development and disrupt maturation of inhibitory neural circuits in schizophrenia.

    “These considerations suggest that reduced availability of CSPGs, perhaps in part due to genetic factors, may lead to a failure to form PNNs during late development, potentially disrupting the maturation of inhibitory neural circuits in SZ.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Metzincin metalloproteases (MMPs, ADAMs, ADAMTS) are the main agents of ECM remodeling and cleave ECM molecules including PNN components.

    “The main agents of this remodeling process are three families of metalloproteases collectively known as metzincin family, i.e. ‘matrix metalloproteases’ (MMPs), ‘a disintegrin and matrix metalloproteases’ (ADAMS), and ‘ADAMS with a thrombospondin domain’ (ADAMTS), which cleave ECM molecules, including those that compose PNNs (Fig.2)”
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    • cites Abdolmaleky et al., 2005b

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    • cites Medina-Flores et al., 2004

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    Premisecitation

    Stress and immune responses have been linked to schizophrenia pathogenesis, and a recent study indicates a genetic contribution to immune factor involvement.

    “These responses have been linked to the pathogenesis of SZ, with a very recent study pointing to a genetic contribution to immune factors involvement (Arion et al., 2007; Fillman et al., 2013; Horvath and Mirnics, 2014; Ripke and Schizophrenia Working Group of the Psychiatric Genomics, 2014; Saetre et al., 2007; Smith et al., 2007).”
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    Interpretationreasoning

    In schizophrenia, interactions between dysregulated stress response and immune systems may alter metalloprotease expression and lead to PNN degradation.

    “Thus, interactions between disregulated stress response and immune systems in subjects with SZ may impact expression of metalloproteases, resulting in degradation of PNNs.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mechanisms of PNN regulation and metalloprotease function found in animal and non-schizophrenia studies apply to human schizophrenia.

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    Premisecitation

    During contextual fear learning, MMP9 levels rise in the amygdala, prefrontal cortex, and hippocampus, and pharmacological MMP blockade impairs reconsolidation of fear memory.

    “For instance, expression of MMP9 was shown to increase in the amygdala, prefrontal cortex, and hippocampus during contextual fear learning, while pharmacological disruption of MMP activity results in disruption of reconsolidation of fear memory (Brown et al., 2009; Ganguly et al., 2013).”
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    • cites Brown et al., 2009

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    Interpretationreasoning

    Altered metalloprotease expression during development and/or adulthood would dysregulate ECM remodeling, causing failed PNN maturation and impaired PNN stability.

    “Altered metalloproteases expression, during development and/or adulthood, would result in dysregulation of ECM remodeling with consequent failure of PNN maturation and impaired PNN stability.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mechanisms of PNN regulation and metalloprotease function found in animal and non-schizophrenia studies apply to human schizophrenia.
    • Rests on an assumption: Changes in mRNA levels of MMPs and ADAMTSs in schizophrenia indicate corresponding changes in protease activity that can degrade PNNs.

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    Premisecitation

    Metalloproteases are key in synaptic plasticity and memory by transiently relieving ECM constraints on plasticity and promoting synaptogenesis.

    “Notably, metalloproteases play a key role in synaptic plasticity and memory, creating windows of opportunity for learning by temporarily releasing neurons from the ECM clamping effects on plasticity and increasing synaptogenesis (Frischknecht and Gundelfinger, 2012; Rivera et al., 2010; Van Hove et al., 2012; Wright and Harding, 2009).”
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    • cites Frischknecht and Gundelfinger, 2012 source

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    • cites Rivera et al., 2010

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    Interpretationreasoning

    PNN abnormalities may be an important factor in schizophrenia pathophysiology and may contribute to the GABAergic circuit disruption observed in the disorder.

    “PNN abnormalities may represent an important factor in the pathophysiology of SZ, contributing to a disruption of GABAergic circuits observed in this disorder.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mechanisms of PNN regulation and metalloprotease function found in animal and non-schizophrenia studies apply to human schizophrenia.
    • Rests on an assumption: Changes in mRNA levels of MMPs and ADAMTSs in schizophrenia indicate corresponding changes in protease activity that can degrade PNNs.

  • May combine two claims.

    Interpretationreasoning

    These PNN abnormalities may influence postnatal neuronal maturation, defense against oxidative stress, synaptic control, and the plasticity of specific interneuron groups, possibly explaining molecular and functional abnormalities in intrinsic inhibitory circuits.

    “and in turn impact postnatal neuronal maturation, protection from oxidative stress, synaptic regulation and plasticity of distinct interneuronal populations, potentially accounting for molecular and functional anomalies in intrinsic inhibitory circuits.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Mechanisms of PNN regulation and metalloprotease function found in animal and non-schizophrenia studies apply to human schizophrenia.
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  • The paper relies on this without support.

    Mechanisms of PNN regulation and metalloprotease function found in animal and non-schizophrenia studies apply to human schizophrenia.

    “For instance, expression of MMP9 was shown to increase in the amygdala, prefrontal cortex, and hippocampus during contextual fear learning, while pharmacological disruption of MMP activity results in disruption of reconsolidation of fear memory (Brown et al., 2009; Ganguly et al., 2013).”

  • The paper relies on this without support.

    Changes in mRNA levels of MMPs and ADAMTSs in schizophrenia indicate corresponding changes in protease activity that can degrade PNNs.

    “Consistent with this hypothesis, a recent gene expression profiling study of the superior temporal gyrus in subjects with SZ showed altered mRNA expression of MMPs and ADAMTSs, including MMP16 (Pietersen et al., 2014).”
2 of 2

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?

Cites

1 retracted

Flagged first, then by citations

3 of the 189 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. Carulli, 2013, Modulation of semaphorin3A in perineuronal nets during structural plasticity in the adult cerebellum, Mol. Cell. Neurosci., 57C, 10, 10.1016/j.mcn.2013.08.003 · DOI · Paper page
  2. Golgi, 1898, Intorno alla struttura delle cellule nervose, Boll. Soc. Med. Chir. Pavia, 1, 1
  3. Vo, 2013, The chemorepulsive axon guidance protein semaphorin3A is a constituent of perineuronal nets in the adult rodent brain, Mol. Cell. Neurosci., 56, 186, 10.1016/j.mcn.2013.04.009 · DOI

Cited by

Sorted by citations

Related

Authors
Berretta, S., Pantazopoulos, H., Markota, M., Brown, C., & Batzianouli, E. T.
Affiliations
  • Harvard University (US)
  • McLean Hospital (US)
Corresponding author
Berretta, Sabina
ORCID
Venue
Schizophrenia Research
Publisher
Elsevier BV
Published
2015-09
Volume
167
Issue
1-3
Pages
18-27
ISSN
0920-9964 (ISSN-L)
DOI
10.1016/j.schres.2014.12.040
PMC
PMC4504843
OpenAlex
W2067214903
Semantic Scholar
c81328ae42747c9add123967a8c1386cf4efc26a
Cited by
152
References
189
Citations by year
2026: 5 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 15 · 2021: 20 · 2020: 8 · 2019: 12 · 2018: 23 · 2017: 24 · 2016: 14 · 2015: 9
FWCI
3.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Schizophrenia Research (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
Funders
National Institute of Mental Health (MH091348, MH083222, MH086522, R01MH091348, R01MH086522, R21MH083222)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
perineuronal nets, schizophrenia
MeSH terms
Animals, Brain, Extracellular Matrix, gamma-Aminobutyric Acid, Humans, Interneurons, Schizophrenia

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.

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