Developmental Pattern of Perineuronal Nets in the Human Prefrontal Cortex and Their Deficit in Schizophrenia

Disruption of PNNs has been particularly well documented in schizophrenia, with marked decreases of CSPG-labeled PNNs in the amygdala, entorhinal cortex and PFC.

“Disruption of PNNs has been particularly well documented in schizophrenia, with marked decreases of CSPG--labeled PNNs in the amygdala, entorhinal cortex and PFC (Pantazopoulos et al., 2010a;Mauney et al., 2013;Pantazopoulos et al., 2015).”

A deficit in the number of PNNs has been described in the PFC of schizophrenic and bipolar patients.

“a deficit in the number of PNNs has been described in the PFC of schizophrenic (Mauney et al., 2013) and bipolar patients (Alcaide et al., 2019)”

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).”

SZ patients have lower density of perineuronal nets (PNN) in PFC.

“and lower density of perineuronal nets (PNN) - extracellular structures that stabilize synapses, also suggesting synaptic loss or destabilization 158.”

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)”

CSPGs are involved in the pathophysiology of schizophrenia.

“Emerging evidence from human postmortem, animal model and genetic studies points to their involvement in the pathophysiology of schizophrenia (SZ).1, 2, 3, 4, 5, 6, 7”

PNNs labeled with WFA are decreased in the amygdala, entorhinal cortex and prefrontal cortex, but not visual cortex, of subjects with schizophrenia.

“Specifically, PNNs labeled with a lectin CSPG marker, that is, Wisteria floribunda agglutinin (WFA), are decreased in the amygdala, entorhinal cortex and prefrontal cortex, but not visual cortex, of subjects with this disorder.3, 4”

PNNs are formed during late postnatal development, a time period coinciding with the typical onset of psychoses.

“PNNs are formed during late postnatal development,4, 26 a time period coinciding with the typical onset of psychoses.”

PNN maturation during late postnatal development contributes to the closure of critical periods of development, stabilizing successful synaptic connectivity and instating a restricted mode of synaptic plasticity characteristic of adulthood.

“PNN maturation during late postnatal development contributes to the closure of critical periods of development, stabilizing successful synaptic connectivity and instating a restricted mode of synaptic plasticity characteristic of adulthood.4, 23, 82, 83, 84”

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).”

Loss of parvalbumin neurons probably does not explain the reported perineuronal net reductions.

“and reported losses of PNNs (Mauney et al, 2013) are not likely due to loss of PV neurons.”

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)).”

In comparison subjects, parvalbumin neurons and perineuronal nets (WFA- or aggrecan-labeled) were densest in layer 3 of dorsolateral prefrontal cortex area 9.

“In the comparison subjects, qualitative analyses revealed that PV neurons and PNNs (identified by WFA labeling or aggrecan immunoreactivity) were present in greatest density in layer 3 of DLPFC area 9 (Figure 1a-1), consistent with prior findings (Hashimoto et al, 2003;Mauney et al, 2013).”

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).”

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.”

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.”

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).”

Perineuronal nets are markedly altered in people with schizophrenia.

“Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia.”

Human postmortem studies show involvement of PNNs in schizophrenia.

“Emerging evidence from human postmortem studies highlights the involvement of PNNs in schizophrenia (SZ) (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”

A similar disruption of inhibitory activity may occur in subjects with schizophrenia in brain regions affected by PNN abnormalities, such as the amygdala, entorhinal cortex, and prefrontal cortex.

“We suggest that a similar disruption of inhibitory activity may occur in subjects with SZ in brain regions affected by PNN abnormalities, such as the amygdala, entorhinal cortex and prefrontal cortex (Mauney et al., 2013; Pantazopolous et al., 2014; Pantazopoulos et al., 2010).”

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).”

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).”

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).”

Postnatal formation of PNNs coincides with maturation of parvalbumin neurons and gamma activity.

“the maturation of parvalbumin neurons and gamma is concurrent with the postnatal developmental formation of perineuronal nets (PNNs) (Mauney et al., 2013)”

Human PNNs occur in the entorhinal cortex, amygdala, hippocampus, visual and prefrontal cortices, and motor and somatosensory cortex.

“in humans, PNNs have also been found to be present in a variety of brain regions, including entorhinal cortex (Pantazopoulos et al., 2010), amygdala (Pantazopoulos et al., 2008; Pantazopoulos et al., 2010), hippocampus (Lendvai et al., 2013), motor and somatosensory cortex (Hausen et al., 1996), visual cortex (Mauney et al., 2013; Murakami et al., 1994; Seeger et al., 1996) and prefrontal cortex (”

In human prefrontal cortex, PNN counts rise across the peripubertal years and continue into late adolescence and early adulthood.

“we have recently shown that the number of PNNs in the human prefrontal cortex also increases through the peripubertal period until late adolescence and early adulthood (Mauney et al., 2013)”

PNNs may be involved in the pathophysiology of schizophrenia.

“Recent evidence suggests that PNNs may also be involved in the pathophysiology of schizophrenia.”

Human post-mortem studies show disease-specific reduction in PNN density and altered expression of genes regulating PNNs/ECM in amygdala, olfactory epithelium, entorhinal cortex, superior temporal cortex, and prefrontal cortex in schizophrenia.

“a number of human post-mortem brain studies have revealed a disease-specific reduction in the density of PNNs as well as altered expression of genes that regulate PNNs and ECM in key brain structures associated with schizophrenia, including the amygdala, olfactory epithelium, entorhinal cortex, superior temporal cortex and prefrontal cortex”

A PNN deficit is present in the prefrontal cortex of schizophrenia patients.

“Given the PNN deficit observed in the prefrontal cortex of patients with schizophrenia (Mauney et al., 2013)”

The perineuronal net surrounding many parvalbumin interneurons is reduced in the dorsolateral prefrontal cortex, entorhinal cortex, and amygdala of schizophrenia patients.

“Moreover, the extracellular matrix (perineuronal net: PNN) that surrounds many PVI is reduced in DLPFC (Mauney et al., 2013), entorhinal cortex, and amygdala of schizophrenia patients (Pantazopoulos et al., 2010).”