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Cited by 223Schizophrenia research and treatmentNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia

Open access
Enwright, John F, Sanapala, Sowmya, Foglio, Aaron, Berry, Raissa, Fish, Kenneth N, Lewis, David A·2016·Neuropsychopharmacology
DOI 10.1038/npp.2016.24PMC PMC4946056
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Abstract

Alterations in cortical parvalbumin (PV)-containing neurons, including a reduced density of detectable neurons and lower PV levels, have frequently been reported in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects. Most PV neurons are surrounded by perineuronal nets (PNNs) and the density of PNNs, as detected by Wisteria floribunda agglutinin (WFA) labeling, has been reported to be lower in schizophrenia. However, the nature of these PNN alterations, and their relationship to disease-related changes in PV neurons, has not been assessed. Using confocal microscopy, we quantified the densities and fluorescence intensities of PV neurons and PNNs labeled with WFA or immunoreactive for the major PNN protein, aggrecan, in the DLPFC from schizophrenia and matched comparison subjects. In schizophrenia, the densities of PV cells and of PNNs were not altered; however, the fluorescence intensities of PV immunoreactivity in cell bodies and of WFA labeling and aggrecan immunoreactivity in individual PNNs around PV cells were lower. These findings indicate that the normal complements of PV cells and PNNs are preserved in schizophrenia, but the levels of PV protein and of individual PNN components, especially the carbohydrate moieties on proteoglycans to which WFA binds, are lower. Given the roles of PV neurons in regulating DLPFC microcircuits and of PNNs in regulating PV cellular physiology, the identified alterations in PV neurons and their PNNs could contribute to DLPFC dysfunction in schizophrenia.

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Crossref · 10.1038/npp.2016.24

Cites

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Claims the paper makes

0 of 61 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The density of parvalbumin cells seen under high magnification is not affected by disease status.

    “(b) The density of PV cells seen under high magnification is not affected by disease status.”
    Quote in the paperSubstantial claim
  • Findingown data

    Parvalbumin soma size did not vary by diagnosis in cells with or without perineuronal nets.

    “and there was no effect of diagnosis on PV soma size in cells with (F 1,27 = 2.2, P = 0.147; Figure 3c) or lacking PNNs (F 1,27 = 2.2, P = 0.148; Figure 3d).”
    Quote in the paperSubstantial claim
  • Findingown data

    With Bonferroni correction within each comorbid factor, no PV or PNN labeling measure varied among schizophrenia subjects by sex, tobacco use at death, antidepressant/benzodiazepine/valproate use at death, or schizoaffective diagnosis.

    “After Bonferroni correction for multiple comparisons (n = 7 dependent measures, resulting in a corrected significant P-value = 0.0071) within each comorbid factor, no measures of PV or PNN labeling differed between schizophrenia subjects as a function of sex, tobacco use at the time of death, use of antidepressants or benzodiazepines and/or sodium valproate at the time of death, or a diagnosis of”
    Quote in the paperSubstantial claim
  • Findingown data

    Fewer parvalbumin-positive cells had aggrecan-positive perineuronal nets in schizophrenia (76.7%) than in comparison (80.6%) subjects (F=13.0, p=0.001).

    “The mean percentage of PV-positive cells with aggrecan-positive PNNs (Figure 4b) was also lower (F 1,26 = 13.0,P = 0.001) in schizophrenia (76.7 ± 5.6%) relative to comparison subjects (80.6 ± 3.8%), although the magnitude of the difference was much smaller than the reduction seen for WFA-positive PNNs.”
    Quote in the paperSubstantial claim
  • Findingown data

    At high magnification, parvalbumin cell density was similar in schizophrenia (3032 cells per mm3) and comparison (3060 cells per mm3) subjects.

    “However, under high magnification, mean PV cell density did not differ (F 1,20 = 0.0, P = 0.88; Figure 2b) between schizophrenia (3032 ± 634 cells per mm 3 ) and comparison (3060 ± 605 cells per mm 3 ) subjects.”
    Quote in the paperSubstantial claim
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 18
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    At low magnification, fewer parvalbumin-positive cells had WFA-positive perineuronal nets in schizophrenia (53.5%) than in comparison (64.6%) subjects (F=6.1, p=0.02), but this was not significant in the unpaired ANCOVA.

    “At low magnification, the mean percentage of PV-positive cells with WFA-positive PNNs in schizophrenia subjects (53.5 ± 24.7%) was lower (F 1,27 = 6.1, P = 0.02) compared with that in comparison subjects (64.6 ± 20.4%), although this did not achieve statistical significance in the unpaired ANCOVA (Supplementary Table 2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    WFA and aggrecan labels overlapped in almost every perineuronal net.

    “High magnification analyses confirmed that WFA and aggrecan labeling colocalized within nearly all PNNs (Figure 1c-4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Most perineuronal nets encircled parvalbumin neurons, many parvalbumin neurons had nets, and a few pyramidal cells also had nets.

    “Many PV neurons were surrounded by PNNs and the majority of PNNs surrounded PV neurons; however, some PCs were also surrounded by PNNs (Figure 1b-4).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In schizophrenia subjects who died by suicide, parvalbumin immunoreactivity was higher in the somata of parvalbumin cells without perineuronal nets.

    “Schizophrenia subjects who committed suicide had higher PV immunoreactivity in the soma of PV cells lacking PNNs (Supplementary Table 3), a finding of uncertain significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In human dorsolateral prefrontal cortex layer 3, most parvalbumin neurons are surrounded by perineuronal nets detected by both aggrecan and Wisteria floribunda agglutinin labeling, while some parvalbumin neurons lack perineuronal nets labeled by either marker.

    “High magnification images (using a × 60 objective) showing that most PV neurons are ensheathed by PNNs (arrows) detected with both aggrecan and WFA labeling and that some PV neurons (notched arrowheads) lack PNNs labeled with either aggrecan or WFA.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Soma parvalbumin labeling in parvalbumin cells is lower in schizophrenia subjects among parvalbumin cells lacking a perineuronal net.

    “and (d) PV cells lacking a PNN.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Parvalbumin mRNA is reduced in schizophrenia, with the decrease specific to layers 3 and 4.

    “lower levels of PV mRNA specifically in layers 3 and 4 (Fung et al, 2010;Hashimoto et al, 2003)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fung et al, 2010 source

      Not checked in the free run.

    • cites Hashimoto et al, 2003 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Schizophrenia is associated with fewer dendritic spines on pyramidal cells, particularly in deep layer 3 of the dorsolateral prefrontal cortex.

    “These alterations include reduced dendritic spine density on PCs, specifically in deep layer 3 (Glantz and Lewis, 2000)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Glantz and Lewis, 2000 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Reports indicate that WFA-labeled perineuronal net density is much lower in schizophrenia entorhinal and prefrontal cortices.

    “The density of PNNs labeled with Wisteria floribunda agglutinin (WFA), a lectin that binds to specific carbohydrate moieties on proteoglycans, has been reported to be markedly lower in the entorhinal and prefrontal cortices in schizophrenia (Mauney et al, 2013;Pantazopoulos et al, 2010Pantazopoulos et al, , 2015)).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Mauney et al, 2013 source

      Not checked in the free run.

    • cites Pantazopoulos et al, 2010 source

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    • cites Pantazopoulos et al, 2015 source

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    • Rests on an assumption: The lectin WFA recognizes particular sugar groups on proteoglycans.

  • May combine two claims.

    Interpretationown data

    In schizophrenia, perineuronal nets around parvalbumin neurons persist, yet reduced amounts of their components make them less detectable at low magnification.

    “Taken together, these findings indicate that PNNs surrounding PV neurons are preserved in schizophrenia, but that lower levels of PNN components render them more difficult to detect under low magnification.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Perineuronal nets enwrap most cortical parvalbumin neurons and a few pyramidal cells.

    “Most cortical PV neurons, and a small number of PCs, are ensheathed by perineuronal nets (PNNs), a condensed form of extracellular matrix (Berretta et al, 2015)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Berretta et al, 2015 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Capture exposure times were set to avoid saturation in every channel and stack, and exposure differences were corrected before processing.

    “Specifically, exposure times during image capture were optimized to prevent saturating conditions for each channel in each image stack and differences in exposure times were corrected before processing.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Lecticans, a group of perineuronal net proteoglycans, carry many sugar groups; aggrecan is especially abundant in mature nets.

    “Several PNN proteoglycans, the lecticans, are highly glycosylated, and one, aggrecan, is highly enriched in mature PNNs (Bitanihirwe and Woo, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bitanihirwe and Woo, 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Perineuronal nets help close critical periods, modulate synaptic plasticity, and respond to oxidative stress.

    “involved in the closure of developmental critical periods, regulation of synaptic plasticity, and are altered by oxidative stress (Cabungcal et al, 2013b;McRae and Porter, 2012)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Cabungcal et al, 2013b

      Not checked in the free run.

    • cites McRae and Porter, 2012 source

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  • May combine two claims.

    Study design and conductown data

    Mean age, postmortem interval, and tissue storage time were similar between the schizophrenia and comparison groups.

    “Subject groups did not differ in mean age, PMI, or tissue storage time (Table 1 and Supplementary Table 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    A power analysis based on prior findings determined how many parvalbumin neurons were sampled.

    “Before low magnification imaging, a power analysis of the number of cells needed to detect a difference in PV cell density, based on prior findings (Beasley et al, 2002), was used to determine the total number of PV neurons to sample.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Beasley et al, 2002 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Every schizophrenia or schizoaffective subject was paired with an unaffected comparison subject on sex and, as closely as possible, on age and postmortem interval.

    “Each subject with schizophrenia (n = 20) or schizoaffective disorder (n = 8) was matched to one unaffected comparison subject for sex and as closely as possible for age and postmortem interval (PMI).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The data indicate that parvalbumin cell density is not altered in schizophrenia, but lower parvalbumin protein levels make parvalbumin cells harder to detect at low magnification.

    “These data indicate that PV cell density is not altered in schizophrenia, but that lower PV protein levels make PV cells more difficult to detect under low magnification.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Although parvalbumin cell and perineuronal net densities are not lower in schizophrenia, lower parvalbumin, aggrecan, and WFA labeling points to a disease process in this dorsolateral prefrontal cortex layer 3 circuit component.

    “Although the density of PV cells and of the PNNs that surround them are not lower in schizophrenia, lower levels of PV, aggrecan, and WFA labeling clearly indicate a pathological process in this component of DLPFC layer 3 circuitry.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Measurements of parvalbumin and perineuronal net labeling in postmortem tissue reflect the levels that were present before death.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Slide codes kept the experimenter unaware of diagnosis.

    “All slides were coded so that the experimenter was blinded to diagnosis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    After deconvolution, each channel's intensity histogram was set identically across subjects, allowing parvalbumin cells and perineuronal nets to be masked under the same conditions.

    “Images were subjected to deconvolution and intensity histograms for each channel were independently adjusted to identical settings across all subjects allowing PV-positive cells and PNNs to be masked under identical conditions across all subjects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The results support that parvalbumin cells and perineuronal nets persist in schizophrenia and that aggrecan immunoreactivity detects perineuronal nets more sensitively than WFA labeling does.

    “Taken together, these findings are consistent with both the persistence of PV cells and PNNs in schizophrenia and a greater sensitivity of aggrecan immunoreactivity than WFA labeling for detecting PNNs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Paired and unpaired ANCOVA models both assessed diagnosis effects on each dependent variable; the paired model supplied reported values since the two models agreed except where noted.

    “Two analyses of covariance (ANCOVA) models (paired and unpaired) were used as described previously (Glausier et al, 2015) to test the effect of diagnosis on each dependent variable.All reported values are from the paired ANCOVA as both models yielded similar results (except where noted in the text).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Glausier et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The current report's findings match the pattern of lower parvalbumin mRNA expression without a change in detectable parvalbumin cell number after perineuronal net disruption.

    “findings that match the current report.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Altered sulfation of N-acetylgalactosamine results in greatly reduced Wisteria floribunda agglutinin labeling.

    “For example, altered sulfation of N-acetylgalactosamine (GalNAc, a major disaccharide found in CSPGs) results in greatly reduced WFA labeling (Miyata et al, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Miyata et al, 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Higher levels of oxidative stress have been reported in schizophrenia.

    “Higher levels of oxidative stress have been reported in schizophrenia (Wang et al, 2009;Yao et al, 2006)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Wang et al, 2009 source

      Not checked in the free run.

    • cites Yao et al, 2006 source

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  • May combine two claims.

    Interpretationcitation

    Each of these factors could affect the excitability of parvalbumin neurons and contribute to lower expression of activity-dependent genes, such as Zif268 and GAD67, in parvalbumin neurons.

    “Each of these factors could affect the excitability of PV neurons and contribute to lower expression of activity-dependent genes, such as Zif268 and GAD67 (Kimoto et al, 2014), in PV neurons.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kimoto et al, 2014 source

      Not checked in the free run.

    • Rests on an assumption: That the functional roles of parvalbumin and perineuronal nets established in other brain regions and cell types apply to layer 3 parvalbumin neurons in the dorsolateral prefrontal cortex.

  • May combine two claims.

    Premisecitation

    Parvalbumin cells with perineuronal nets are highly enriched for markers involved in matrix remodeling, suggesting these cells may be particularly susceptible to extracellular matrix alterations.

    “Moreover, two distinct populations of PV neurons have recently been interrogated based on the presence of PNNs, and the PV cells with PNNs (which are the majority of PV neurons) are highly enriched for markers involved in matrix remodeling (Rossier et al, 2015), suggesting these cells may be particularly susceptible to ECM alterations.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rossier et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Perineuronal nets carry a high degree of negative charge and may function as cation sinks.

    “First, PNNs carry a high degree of negative charge and may function as cation sinks (Bruckner et al, 1993).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bruckner et al, 1993 source

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    Premisecitation

    Aggrecan expression and glycosylation state are activity-dependent.

    “In addition, both aggrecan expression (McRae et al, 2010) and glycosylation state (Lander et al, 1997) are activity-dependent.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites McRae et al, 2010 source

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    • cites Lander et al, 1997 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Expression of several enzymes involved in extracellular matrix degradation is increased in the temporal cortex in schizophrenia.

    “Interestingly, the expression of several enzymes involved in extracellular matrix (ECM) degradation is increased in the temporal cortex in schizophrenia (Pietersen et al, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pietersen et al, 2014 source

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  • May combine two claims.

    Premisecitation

    Experimental disruptions of perineuronal nets result in lower parvalbumin mRNA expression without a change in the number of detectable parvalbumin cells.

    “Any of these mechanisms could lead to lower PV levels as experimental disruptions of PNNs results in lower PV mRNA expression (Yamada et al, 2015), without a change in the number of detectable PV cells (Cabungcal et al, 2013a), findings that match the current report.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Yamada et al, 2015 source

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    • cites Cabungcal et al, 2013a

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    Premisecitation

    Mice lacking parvalbumin have behavioral deficits, including altered social interactions.

    “Moreover, mice lacking PV have behavioral deficits, including altered social interactions (Wohr et al, 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wohr et al, 2015 source

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  • May combine two claims.

    Premisecitation

    Parvalbumin is a low-affinity calcium buffer that likely regulates neurotransmitter release.

    “PV is a low-affinity calcium buffer that likely regulates neurotransmitter release (Eggermann and Jonas, 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Eggermann and Jonas, 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dorsolateral prefrontal cortex layer 3 pyramidal cells appear to receive fewer excitatory synaptic inputs, resulting in lower expression of gene products critical for energy production.

    “Because DLPFC layer 3 PCs appear to receive fewer excitatory synaptic inputs (Glantz and Lewis, 2000) resulting in a lower expression of gene products critical for energy production (Arion et al, 2015)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Glantz and Lewis, 2000 source

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    • cites Arion et al, 2015 source

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  • May combine two claims.

    Premisecitation

    Increased oxidative stress in an animal model results in lower Wisteria floribunda agglutinin labeling of perineuronal nets and alterations in gamma oscillations.

    “and increased oxidative stress in an animal model results in lower WFA labeling of PNNs and alterations in γ-oscillations (Cabungcal et al, 2013a, b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cabungcal et al, 2013a, b

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Perineuronal nets might undergo enhanced degradation in schizophrenia.

    “Furthermore, PNNs might be subject to enhanced degradation in schizophrenia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Disruption of perineuronal nets can alter the resting membrane potential of parvalbumin neurons and decrease the amplitudes of both inhibitory and excitatory postsynaptic currents.

    “Fourth, disruption of PNNs can alter the resting membrane potential of PV neurons (Miyata et al, 2012) and decrease the amplitudes of both inhibitory (Liu et al, 2013) and excitatory (Pyka et al, 2011) postsynaptic currents.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Miyata et al, 2012 source

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    • cites Liu et al, 2013

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    • cites Pyka et al, 2011 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Cabungcal et al, 2013a

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    • cites Do et al, 2015

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    • cites Morishita et al, 2015 source

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  • May combine two claims.

    Premisecitation

    Loss of extracellular matrix components increases the mobility of excitatory AMPA receptors, potentially altering the ability of glutamatergic inputs to depolarize the cell.

    “Third, the loss of ECM components increases the mobility of excitatory AMPA receptors (Frischknecht et al, 2009), potentially altering the ability of glutamatergic inputs to depolarize the cell.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Frischknecht et al, 2009 source

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  • May combine two claims.

    Interpretationreasoning

    Reductions in parvalbumin could result in altered GABA release and inhibition of pyramidal neurons in the dorsolateral prefrontal cortex and contribute to the clinical features of schizophrenia.

    “Therefore, reductions in PV could result in altered GABA release and inhibition of pyramidal neurons in the DLPFC and contribute to the clinical features of schizophrenia.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: That lower parvalbumin and perineuronal net labeling measured in postmortem dorsolateral prefrontal cortex reflects antemortem differences in these components rather than postmortem or tissue-processing effects.
    • Rests on an assumption: That findings from rodent models, such as parvalbumin knockout or perineuronal net disruption, are applicable to human dorsolateral prefrontal cortex parvalbumin neurons in schizophrenia.
    • Rests on an assumption: That the functional roles of parvalbumin and perineuronal nets established in other brain regions and cell types apply to layer 3 parvalbumin neurons in the dorsolateral prefrontal cortex.

  • May combine two claims.

    Premisecitation

    Parvalbumin is important in short-term plasticity in striatal neurons, and loss of parvalbumin can affect the excitability and output of these cells.

    “Furthermore, PV is important in short-term plasticity in striatal neurons and loss of PV can affect the excitability and output of these cells (Orduz et al, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Orduz et al, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Parvalbumin- and perineuronal-net-mediated alterations are likely to contribute to dysfunction of the layer 3 parvalbumin-pyramidal cell local circuitry that generates gamma oscillations and thus to the neural basis for impairments in dorsolateral prefrontal cortex gamma oscillations seen during cognitive tasks in individuals with schizophrenia.

    “Through a variety of mechanisms, PV and PNN-mediated alterations are likely to contribute to dysfunction of the layer 3 PV-PC local circuitry that generates γ-oscillations (Gonzalez-Burgos et al, 2015) and thus to the neural basis for the impairments in DLPFC γ-oscillations seen during cognitive tasks in individuals with schizophrenia (Uhlhaas and Singer, 2015).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gonzalez-Burgos et al, 2015 source

      Not checked in the free run.

    • cites Uhlhaas and Singer, 2015 source

      Not checked in the free run.

    • Rests on an assumption: That lower parvalbumin and perineuronal net labeling measured in postmortem dorsolateral prefrontal cortex reflects antemortem differences in these components rather than postmortem or tissue-processing effects.
    • Rests on an assumption: That findings from rodent models, such as parvalbumin knockout or perineuronal net disruption, are applicable to human dorsolateral prefrontal cortex parvalbumin neurons in schizophrenia.
    • Rests on an assumption: That the functional roles of parvalbumin and perineuronal nets established in other brain regions and cell types apply to layer 3 parvalbumin neurons in the dorsolateral prefrontal cortex.
43 of 43

  • The paper relies on this without support.

    The lectin WFA recognizes particular sugar groups on proteoglycans.

    “a lectin that binds to specific carbohydrate moieties on proteoglycans”

  • The paper relies on this without support.

    Measurements of parvalbumin and perineuronal net labeling in postmortem tissue reflect the levels that were present before death.

    “The lower levels of PV protein and of PNN markers appear to reflect the disease process”

  • The paper relies on this without support.

    The effects of chronic haloperidol on parvalbumin and perineuronal net labeling in monkeys can be generalized to antipsychotic effects in schizophrenia subjects.

    “we looked at potential effects of these medications in adult monkeys chronically exposed to the antipsychotic haloperidol”

  • The paper relies on this without support.

    That lower parvalbumin and perineuronal net labeling measured in postmortem dorsolateral prefrontal cortex reflects antemortem differences in these components rather than postmortem or tissue-processing effects.

    “Our observation that the level of PV protein per neuron, and not the number of PV neurons, is lower in schizophrenia may have the following functional consequences.”

  • The paper relies on this without support.

    That findings from rodent models, such as parvalbumin knockout or perineuronal net disruption, are applicable to human dorsolateral prefrontal cortex parvalbumin neurons in schizophrenia.

    “In contrast, our findings of a positive correlation between PV and PNN labeling is unlikely to be due to lower PV expression causing lower PNN labeling because mice lacking PV have normal WFA labeling (Schwaller et al, 2004).”

  • The paper relies on this without support.

    That the functional roles of parvalbumin and perineuronal nets established in other brain regions and cell types apply to layer 3 parvalbumin neurons in the dorsolateral prefrontal cortex.

    “PV is a low-affinity calcium buffer that likely regulates neurotransmitter release (Eggermann and Jonas, 2012).”
6 of 6

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?

  • Alterations of prefrontocortical PV1 interneurons and PNNs have been described in schizophrenia or bipolar disorder.

    “in which alterations of prefrontocortical PV1 interneurons and PNNs have been described (Mauney et al., 2013;Enwright et al., 2016;Alcaide et al., 2019).”

    From Perineuronal Nets Regulate the Inhibitory Perisomatic Input onto Parvalbumin Interneurons and γ Activity in the Prefrontal Cortex (2020) · cites this paper as Enwright et al., 2016

  • Post-mortem brains from patients with schizophrenia exhibit reduced density of WFA-labeled cells and reduced levels of CSPGs and PV expression in prefrontal cortex.

    “Post-mortem brains from patients with schizophrenia exhibit reduced density of WFA-labeled cells (Mauney et al., 2013) and reduced levels of CSPGs and PV expression in prefrontal cortex (Enwright et al., 2016).”

    From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Enwright et al., 2016

  • Some human and animal data suggest that PV-INs may remain present but cease to express PV, although a definitive conclusion cannot yet be drawn.

    “Some human and animal model data suggest that formerly PV-INs are still present but cease to express PV, though a definitive conclusion cannot be drawn at this point [7,[18][19][20].”

    From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [19]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Discussion points to a cell-size panel for a density comparison

    Minor

    The discussion cites Figure 3b as evidence that low- and high-magnification PV cell densities are nearly identical. The caption identifies Figure 3b as a distribution of soma cross-sectional area, not a density measurement; Figure 2b is the high-magnification density panel.

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Authors
Enwright, J. F., Sanapala, S., Foglio, A., Berry, R., Fish, K. N., & Lewis, D. A.
Affiliations
University of Pittsburgh (US)
Corresponding author
Lewis, David A
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2016-02-12
Volume
41
Issue
9
Pages
2206-2214
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2016.24
PMC
PMC4946056
OpenAlex
W2268380328
Semantic Scholar
1a2cf80d219f356f74a3c65fccb2588c9026f068
Cited by
223
References
53
Citations by year
2026: 13 · 2025: 28 · 2024: 23 · 2023: 23 · 2022: 17 · 2021: 29 · 2020: 27 · 2019: 17 · 2018: 23 · 2017: 17 · 2016: 6
FWCI
18.64
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (MH043784)
  • National Institute of Mental Health (R01MH043784, P50MH103204, R01MH096985, R37MH043784)
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 › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
schizophrenia, parvalbumin neurons, perineuronal nets, dorsolateral prefrontal cortex, Wisteria floribunda agglutinin, aggrecan, proteoglycans, cortical microcircuits
MeSH terms
Adult, Female, Humans, Immunohistochemistry, Male, Middle Aged, Neurons, Parvalbumins, Schizophrenia, Prefrontal Cortex, Receptors, N-Acetylglucosamine, Plant Lectins

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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.

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