Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala

Abstract

Perineuronal nets (PNNs) are specialized extracellular matrix aggregates surrounding distinct neuronal populations and regulating synaptic functions and plasticity. Previous findings showed robust PNN decreases in amygdala, entorhinal cortex and prefrontal cortex of subjects with schizophrenia (SZ), but not bipolar disorder (BD). These studies were carried out using a chondroitin sulfate proteoglycan (CSPG) lectin marker. Here, we tested the hypothesis that the CSPG aggrecan, and 6-sulfated chondroitin sulfate (CS-6) chains highly represented in aggrecan, may contribute to these abnormalities. Antibodies against aggrecan and CS-6 (3B3 and CS56) were used in the amygdala of healthy control, SZ and BD subjects. In controls, aggrecan immunoreactivity (IR) was observed in PNNs and glial cells. Antibody 3B3, but not CS56, also labeled PNNs in the amygdala. In addition, dense clusters of CS56 and 3B3 IR encompassed CS56- and 3B3-IR glia, respectively. In SZ, numbers of aggrecan- and 3B3-IR PNNs were decreased, together with marked reductions of aggrecan-IR glial cells and CS-6 (3B3 and CS56)-IR ‘clusters'. In BD, numbers of 3B3-IR PNNs and CS56-IR clusters were reduced. Our findings show disruption of multiple PNN populations in the amygdala of SZ and, more modestly, BD. Decreases of aggrecan-IR glia and CS-6-IR glial ‘clusters', in sharp contrast to increases of CSPG/lectin-positive glia previously observed, indicate that CSPG abnormalities may affect distinct glial cell populations and suggest a potential mechanism for PNN decreases. Together, these abnormalities may contribute to a destabilization of synaptic connectivity and regulation of neuronal functions in the amygdala of subjects with major psychoses.

Involvement of chondroitin 6-sulfation in temporal lobe epilepsy

“…12 schizophrenia Pantazopoulos et al, 2015). In a rat model of epilepsy, status epilepticus reduces PNN number and causes structural degradation of PNNs (McRae et al, 2012;McRae and Porter, 2012).…”

“…Dysregulation of PNNs is implicated in various neurological and psychiatric disorders including epilepsy, Alzheimer's disease, bipolar disorder, schizophrenia, and traumatic brain injury (Baig et al, 2005;McRae and Porter, 2012;Morawski et al, 2010;Okamoto et al, 2003;Pantazopoulos et al, 2015;Yi et al, 2012). Additionally, alteration of C6ST-1 expression and CS sulfation patterns are reportedly evident in brains of human patients with bipolar disorder or schizophrenia and mice with cortical brain injury (Okuda et al, 2014;Pantazopoulos et al, 2015;Yi et al, 2012).…”

“…Reportedly, alteration of CS sulfation patterns and/or PNNs is evident in various neurological and psychiatric disorders including epilepsy, Alzheimer's disease, ischemic stroke, bipolar disorder, schizophrenia, and traumatic brain injury(Baig et al, 2005;Bonneh-Barkay and Wiley, 2009;Cabungcal et al, 2013; Hobohm et al, 2005;Okamoto et al, 2003;Pantazopoulos et al, 2015;Swarup et al, 2013;Yi et al, 2012). For example, postmortem analysis of amygdala indicates that 6-sulfated CS chains recognized by CS-56 are less numerous in brains from patients with schizophrenia or bipolar disorder than in control brains.…”

Perineuronal nets labeled by monoclonal antibody VC1.1 ensheath interneurons expressing parvalbumin and calbindin in the rat amygdala

“…Likewise Pantazopoulos and coworkers (2006) found that about one-third of PV+ interneurons in the human basolateral amygdala were ensheathed by WFA+ PNNs, and a subset of these neurons also expressed CB. The finding that there is significant loss of PNNs in the basolateral amygdala of patients with schizophrenia implicates these structures in the dysfunction of GABAergic neurons in this disorder (Pantazopoulos et al, 2010, 2015; Berretta, 2012; Berretta et al, 2015). …”

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

“…Several PNN proteoglycans, the lecticans, are highly glycosylated, and one, aggrecan, is highly enriched in mature PNNs (Bitanihirwe and Woo, 2014). 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.…”