Major Histocompatibility Complex I in Brain Development and Schizophrenia

Abstract

Although the etiology of schizophrenia (SZ) remains unknown, it is increasingly clear that immune dysregulation plays a central role. Genome-wide association studies reproducibly indicate an association of SZ with immune genes within the major histocompatibility complex (MHC). Moreover, environmental factors that increase risk for SZ, such as maternal infection, alter peripheral immune responses as well as the expression of immune molecules in the brain. MHCI molecules may mediate both genetic and environmental contributions to SZ through direct effects on brain development, in addition to mediating immunity. MHCI molecules are expressed on neurons in the central nervous system (CNS) throughout development and into adulthood, where they regulate many aspects of brain development including neurite outgrowth, synapse formation and function, long-term and homeostatic plasticity, and activity-dependent synaptic refinement. This review summarizes our current understanding of MHCI expression and function in the developing brain, as well as its involvement in maternal immune activation, from the perspective of how these roles for MHCI molecules might contribute to the pathogenesis of SZ.

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…However, determining causality can be difficult because of the protracted amount of time between insult and diagnosis . Immune system activation has been implicated as a risk factor for schizophrenia (Horvath and Mirnics, 2014a) and the major histocompatibility complex is the most prominent signal in GWAS studies (McAllister, 2014;Stefansson et al, 2009). MIA in rats and mice causes dysfunction of GABAergic circuitry in the hippocampus, amygdala, and cortex (Canetta and Brown, 2012;Meyer, 2014).…”

“…Over the past two decades, genetic studies of candidate genes implicated multiple disease-predisposing DNA sequence variants in disrupted-in-schizophrenia 1 (DISC1), neuregulin 1 (NRG1), catechol-O-methyl transferase (COMT), regulator of G-protein signaling 4 (RGS4), metabotropic glutamate receptor 3 (GRM3), dysbindin (DTNBP1), G72, and other sequences (Harrison and Weinberger, 2005), yet replications of these findings were quite inconsistent from cohort to cohort. More recently, genome-wide association studies (GWAS) analyzing DNA from tens of thousands of patients with schizophrenia have been identified between one and 'several thousands of common alleles of very small effect' associated with diagnosis (Aberg et al, 2013; Cross-Disorder Group of the Psychiatric Genomics C, Genetic Risk Outcome of Psychosis C, 2013;McAllister, 2014;Purcell et al, 2009;Ripke et al, 2013;Shi et al, 2009;Stefansson et al, 2009), yet these findings showed only a modest overlap with the outcomes of the candidate gene studies. With the expansion of the patient cohorts and development of more sophisticated analytical approaches, the newest GWAS data argue that diverse common alleles accumulate within a pathway and reach a threshold for susceptibility that leads to disease (Horvath and Mirnics, 2014b).…”

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

“…We have proposed that this mechanism underlies the injury of demyelinated axons in multiple sclerosis (MS) 1, 2, 4, 10. Evidence also suggests that MHC I is involved with synaptic pruning during cortical development12, 13, 14, 16, 17, 18, 19, 20, 21 and following injury22, 23, 24, 25 and contributes to neuronal plasticity 16, 17, 26, 27. These findings also suggest that retrogradely induced MHC class I may contribute to the diffuse synaptopathy observed in MS and other neurodegenerative diseases 28, 29, 30, 31, 32, 33, 34, 35.…”

A schizophrenia-associated HLA locus affects thalamus volume and asymmetry

“…Susceptibility arises in part from multiple small effects of genetic variants which are common in the population (Purcell et al, 2014). Among the significant genetic associations found with schizophrenia by genome-wide association scans (GWAS), those within the Human Leukocyte Antigens (HLA) region, on chromosome 6p, are of particular interest because they hint at a role of immunological genes in disease pathogenesis (Andreassen et al, 2014;McAllister, 2014;Stringer et al, 2014). The HLA region, the human homologue of the Major Histocompatibility Complex (MHC) region, spans about 4.5 million base pairs containing more than 200 genes, many of them involved in the immune system, such as those coding for the HLA proteins (Cullen et al, 2002;Shiina et al, 2009).…”

“…In addition, knock-out mice for the homologous immune system show increased ocular dominance, as well as aberrant patterns of Long-Term Potentiation (LTP) and Long-Term Depression (LTD) in the hippocampus (Datwani et al, 2009;Elmer and McAllister, 2012;Huh et al, 2000). As these observations indicate effects of the MHC on thalamus and hippocampus development and function, the possibility also arises that the MHC is involved in dysfunction linked to these structures McAllister, 2014).…”