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.

Shared Immune and Repair Markers During ExperimentalToxoplasmaChronic Brain Infection and Schizophrenia

“…53 Extracellular matrix abnormalities and resulting LTP-like plasticity deficits are likely to contribute to the pathophysiology of schizophrenia and result in impaired information processing in patients. 54,55 Antipsychotic drugs are known to normalize extracellular matrix abnormalities in schizophrenia through epigenetic regulation. 55 The exact role of PAI-1 in T gondii infection and schizophrenia-related mechanisms is unknown.…”

“…54,55 Antipsychotic drugs are known to normalize extracellular matrix abnormalities in schizophrenia through epigenetic regulation. 55 The exact role of PAI-1 in T gondii infection and schizophrenia-related mechanisms is unknown. Similar to TIMP-1, PAI-1 controls the matrix metalloproteinase activity and degradation of extracellular matrix proteins.…”

The involvement of <italic>N</italic>-methyl-d-aspartate receptor (NMDAR) subunit NR1 in the pathophysiology of schizophrenia

“…Evidence also supported the involvement of Reelin, an extracellular matrix (ECM) glycoprotein, in the regulation of NR1 subunits in the pathophysiology of schizophrenia, thus strongly affecting synaptic maturation and stabilization. Reelin has been shown to mediate a switch in the subunits composition of NMDARs, which was considered to be the hallmark of synaptic maturation [118]. In the frontal cortex, Reelin heterozygous mice showed significant downregulation of NR1 subunits.…”

Neurobiology of Schizophrenia Onset

“…Therefore, deficit of PNNs can lead to the dysfunction of PV neurons and thereby gamma band oscillation disturbances. In addition, because PNNs may also play an important role in maintaining the integrity of the connectional architecture of pyramidal cell network by regulating synaptic plasticity (Galtrey and Fawcett 2007;Dityatev et al 2010;Wlodarczyk et al 2011), PNN deficit can directly destabilize synaptic connectivities and thereby contribute to cortical circuitry dysfunction in schizophrenia (Berretta 2012;Pantazopoulos et al 2010;Mauney et al 2013). …”

“…Specifically, it is postulated that the inhibitory neurons that contain PV may play a central role in regulating the time course of PFC synaptic pruning during late adolescence and early adulthood and that disturbances of PV neurons may lead to aberrant loss of synapses and thereby cortical circuitry instability, hence triggering the onset of schizophrenia . In this review, we discuss the possible pathophysiological mechanisms that may contribute to the dysfunction of PV neurons in schizophrenia, focusing on deficient glutamatergic innervation, oxidative stress and impaired formation of ECM structures called perineuronal nets (PNNs) (Behrens and Sejnowski 2009;Do et al 2009;Bitanihirwe and Woo 2011;Berretta 2012).…”