Molecular Evidence for Increased Expression of Genes Related to Immune and Chaperone Function in the Prefrontal Cortex in Schizophrenia

Abstract

We speculate that the overexpression of SERPINA3, IFITM1, IFITM2, IFITM3, CHI3L1, MT2A, CD14, HSPB1, HSPA1B, and HSPA1A in schizophrenia subjects represents a long-lasting and correlated signature of an early environmental insult during development that actively contributes to the pathophysiology of prefrontal dysfunction.

Shared Gene Expression Alterations in Schizophrenia and Bipolar Disorder

“…We find that after careful evaluation with ANCOVA and removal of outlier chips that mitochondrialassociated transcripts were not overrepresented in the SMRI Microarray DLPFC set. Furthermore, immune genes were significantly dysregulated in our study consistent with another recent microarray study (50) in which pH was well-balanced in case and control subjects. Thus, animal models will certainly play a role in determining whether genes that are altered in pH sensitive pathways also convey behavioral-, immune-, and plasticityrelated effects.…”

Predicting Risk and the Emergence of Schizophrenia

“…27 A positive association between elevated maternal levels of the cytokine interleukin-8 during pregnancy and an increased risk of schizophrenia spectrum disorders in the offspring has been found. 22 The findings of immune dysregulation in schizophrenia 28 and evidence of abnormal expression of immune-related genes in postmortem schizophrenia studies 29 support the idea of the maternal immune response as the important mechanism. Animal models of infection have provided evidence that the maternal immune response affects fetal brain development in ways that are consistent with neuropathology seen in schizophrenia.…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…In addition to cellular evidence, changes in the expression of genes with known importance for developmental processes-including cellular migration, synaptogenesis, synaptic maintenance, cell signaling, glia, immune regulation, and mitochondrial function-have been found in postmortem tissue from patients with schizophrenia (Arion et al, 2007(Arion et al, , 2010Clay et al, 2010;Hakak et al, 2001;Harrison and Weinberger, 2005;Horvath and Mirnics, 2014a, b;Jaaro-Peled et al, 2009;Lewis et al, 2005;McGlashan and Hoffman, 2000;Middleton et al, 2002;Mirnics et al, 2000Mirnics et al, , 2001bMirnics and Pevsner, 2004;Roussos et al, 2012). Importantly, multiple studies report expression changes in GABA system-related transcripts, including altered expression of GABA-synthesizing enzymes, glutamic acid decarboxylase 1 and 2 (GAD1 and GAD2, discussed in the next section), interneuronexpressed proteins and neuropeptide genes (PV, CCK, NPY, SST, and CB) (Hashimoto et al, 2003(Hashimoto et al, , 2008aHoftman et al, 2013;Iritani et al, 2000;Kuromitsu et al, 2001;Maldonado-Aviles et al, 2009;Mellios et al, 2009;Volk et al, 2012), GABA receptor subunits (GABRA1-2, GABRA4-6, and GABRD) (Benes et al, 1992;Hashimoto et al, 2008a, b;Hoftman et al, 2013;Maldonado-Aviles et al, 2009;Volk et al, 2002b), and interneuron development-and maintenance-related mRNAs (GABA transporter 1, sodium potassium chloride cotransporter 1 (NKCC1), and KCC2) Fish et al, 2011;Hashimoto et al, 2008a, b;Hoftman et al, 2013;Hyde et al, 2011;Volk et al, 2002b).…”