Extracellular matrix abnormalities in schizophrenia

Abstract

Emerging evidence points to the involvement of the brain extracellular matrix (ECM) in the pathophysiology of schizophrenia (SZ). Abnormalities affecting several ECM components, including Reelin and chondroitin sulfate proteoglycans (CSPGs), have been described in subjects with this disease. Solid evidence supports the involvement of Reelin, an ECM glycoprotein involved in corticogenesis, synaptic functions and glutamate NMDA receptor regulation, expressed prevalently in distinct populations of GABAergic neurons, which secrete it into the ECM. Marked changes of Reelin expression in SZ have typically been reported in association with GABA-related abnormalities in subjects with SZ and bipolar disorder. Recent findings from our group point to substantial abnormalities affecting CSPGs, a main ECM component, in the amygdala and entorhinal cortex of subjects with schizophrenia, but not bipolar disorder. Striking increases of glial cells expressing CSPGs were accompanied by reductions of perineuronal nets, CSPG- and Reelin-enriched ECM aggregates enveloping distinct neuronal populations. CSPGs developmental and adult functions, including neuronal migration, axon guidance, synaptic and neurotransmission regulation are highly relevant to the pathophysiology of SZ. Together with reports of anomalies affecting several other ECM components, these findings point to the ECM as a key component of the pathology of SZ. We propose that ECM abnormalities may contribute to several aspects of the pathophysiology of this disease, including disrupted connectivity and neuronal migration, synaptic anomalies and altered GABAergic, glutamatergic and dopaminergic neurotransmission.

Figure 1. PNNs predominantly surround neurons expressing parvalbumin

Confocal photomicrograph showing PNNs (green) enveloping PVB-positive neurons (red). Scale bar =100 μm. Modified from (Pantazopoulos et al., 2006).

Figure 2. Simplified diagram depicting CSPG synthesis and their secretion into the ECM, and interaction with other ECM molecules

CSPGs are formed by a core protein and a glycosaminoglycan component consisting of chondroitin sulfate chains (versican is represented here as an example). The core protein is synthesized in cytoplasmic ribosomes and then transferred to the Golgi apparatus for glycosylation. Several enzymes concur in adding repeating disaccharide units to form linear polysaccharide chains, which are then polymerized through the activity of chondroitin synthase and chondroitin polymerizing factor. Glycosaminglycan chains are modified by sulfation, packed into secretory vesicles, and released into the ECM, where they interact with a number of other components, such as hyaluronan and tenascins. Denser ECM around a neuron (yellow) represents a PNN.

Figure 3. Marked increased of WFA-labeled elements in subjects with schizophrenia

Photo-composites of sample coronal sections containing amygdala nuclei and ECx from a normal control (A) and a SZ subject (B) show marked WFA-labeling (black reaction product) in SZ. Note increased WFA labeling in subject with SZ. Dashed lines on A indicate the borders of each region (see C). Photomicrographs in D and E show a portion of the superficial layers of the ECx (segment shown in E corresponds to that marked by arrows in B). Photomicrographs in F-I show examples of PVB-IR neurons (F), PNNs (G), WFA-labeled glial cells (H), and GFAP-labeled cells (I). Photomicrographs in G and H are from sections labeled with WFA lectin histochemistry and Nissl-counterstained. PNN (G) net-like labeling is extracellular and surrounds the neurons soma and dendrites. WFA-labeled PNNs are easily distinguishable from WFA-labeled glial cells (H), characterized by intense intracellular labeling showing short “bushy” processes and small cell bodies. Their size and morphological characteristics are instead very similar to those of GFAP-IR astrocytes (I). Black reaction product in A, B, D-I corresponds to nickel-enhanced diaminobenzidine staining. Abbreviations: AA, anterior amygdaloid nucleus; CE, central nucleus; HP, hippocampus; PRCx, perirhinal cortex. Modified from (Pantazopoulos et al., 2010).

Figure 3. Marked increased of WFA-labeled elements in subjects with schizophrenia

Photo-composites of sample coronal sections containing amygdala nuclei and ECx from a normal control (A) and a SZ subject (B) show marked WFA-labeling (black reaction product) in SZ. Note increased WFA labeling in subject with SZ. Dashed lines on A indicate the borders of each region (see C). Photomicrographs in D and E show a portion of the superficial layers of the ECx (segment shown in E corresponds to that marked by arrows in B). Photomicrographs in F-I show examples of PVB-IR neurons (F), PNNs (G), WFA-labeled glial cells (H), and GFAP-labeled cells (I). Photomicrographs in G and H are from sections labeled with WFA lectin histochemistry and Nissl-counterstained. PNN (G) net-like labeling is extracellular and surrounds the neurons soma and dendrites. WFA-labeled PNNs are easily distinguishable from WFA-labeled glial cells (H), characterized by intense intracellular labeling showing short “bushy” processes and small cell bodies. Their size and morphological characteristics are instead very similar to those of GFAP-IR astrocytes (I). Black reaction product in A, B, D-I corresponds to nickel-enhanced diaminobenzidine staining. Abbreviations: AA, anterior amygdaloid nucleus; CE, central nucleus; HP, hippocampus; PRCx, perirhinal cortex. Modified from (Pantazopoulos et al., 2010).