*3.3.2 Extracellular matrix system (ECM)*

Neurons and glial synthesize the ECM, which impacts the maturing and maintenance of synapses. Moreover, at the hyaluronan level, the ECM divides the exterior of neurons, restricting the exterior movement of integrated membrane proteins. In the pathogenesis of SCZ, failures in ECM development have been suggested. The ECM is comprised in part of chondroitin sulfates. Patients diagnosed with SCZ demonstrated a massive rise in chondroitin sulfate proteoglycan (CSPG) - positive glia in the entorhinal cortex and deep amygdala, whereas the density of GFAP − positive cells was not altered. As CSPGs mediate adult synaptic plasticity, higher levels in SCZ could play a role in alterations in this process. Further, modification of the ECM could result in differences in distribution of receptors and transmitters. For example, decreased expression of Reelin, a component of the ECM primarily expressed in adult GABA neurons, was observed in patients with SCZ in caudate nucleus, cerebellum, hippocampus, and prefrontal and temporal cortices. A decrease in Reelin is typically associated with a reduction in glutamic acid decarboxylase expression, suggesting a robust functional correlation between Reelin expression and GABAergic neurotransmission. Consequently, the variations in ECM could be expected to have an impact on release of inhibitory neurotransmitter [119].

## *3.3.3 Epigenetics*

A connection between SCZ risk and epigenetic pathways has been suggested based on association studies. In a study of the promotor hypermethylation status of the glutathione S-transferase TI (GSTT1) and glutathione S-transferase P1 (GSTP1) genes in a Tunisian SCZ population, a significant relationship between SCZ and the GSTT1 and GSTP1 active genotype was noted [120]. A similar relationship was noted in another study [121].

The single nucleotide polymorphisms rs1043618 and rs2075799 in *HSPA1A* (heat shock protein family A "HSP70" member 1A) have been linked to SCZ [122, 123], which is interesting as HSP70 facilitates astrocytic neuroinflammation [124]. No epigenetic processes have been defined that might modulate the expression of HSP70 in SCZ.

Valproic acid (VPA) and other HDAC inhibitors are molecules that facilitate chromatin remodeling to modify gene transcription selectively, such as MS-275, trichostatin A, sodium butyrate, and apicidin appear to enhance H3K4Me3 and H3K4Me2 levels at the *HSP70* astrocytic promoter. H3K4me3 and H3K4me2 are related to transcriptionally active chromatin areas. Curiously, VPA provoked stimulation of the astrocytic *HSP70* promoter through employing histone acetyltransferase p300 in astrocytes of the rat cortex [125].

Moreover, there are data for enhanced *HSPA1A* expression and additional genes associated with immune function, such as the proinflammatory mediators *IFITM2*, *IFITM1*, and *IFITM3* in postmortem dorsolateral prefrontal cortex *(*dlPFC) sections from SCZ [120]. A considerable link was noted between first-episode psychosis in Greek schizophrenic patients and *the HSPA8* variant (rs1136141) [126].

Regulator of G-protein–signaling 4 (RGS4) is a GTPase-triggering protein that regulates G-protein-coupled receptor signaling, regulating receptor-facilitated synaptic neural signaling [127]. A variant of the *RGS4* polymorphism (rs951436) leads to declines in the structural volume of the white matter [128]. Downregulation of *RGS4* transcripts in the dlPFC of SCZ patients has been reported that suggest that this gene could be a candidate gene for SCZ [129].


#### **Table 1.**

*An overview of studies evaluating OMICS approaches for astrocytic abnormalities in SCZ.*

A different study demonstrated that *RSG4* expression of the lengthiest variant, *RGS4-*1, was reduced in schizophrenic patients' dlPFC [130]. The methylation of *RGS4* regulatory region CpG islands in the *postmortem* dlPFC sections was evaluated in SCZ and results showed that the reduced *RGS4-*1 mRNA expression levels were not related to hypermethylation of the 5′ region CpG islands. Moreover, the more deficient *RGS4-*1 expression was associated with the 5′ regulatory regions SNPs rs2661347, rs951436, rs10917670, and rs2661319 [131].

Research by Vrajová *et al*. assessed the potential epigenetic process of *RGS4* expression via silenced *RGS4* gene utilizing siRNA targeted toward human *RGS4* and analyzed the impact of neuroblastoma cell lines differential expression. They noted that downregulated *RGS4* mRNA alters the expression of 67 genes comprising crucial transcription factors, such as brain-derived neurotrophic factor (BDNF) and DISC1, related to the pathology of SCZ [132]. Additionally, several OMICS approaches have evaluated the interaction among astrocytes and SCZ (**Table 1**).
