Circuit- and Diagnosis-Specific DNA Methylation Changes at γ-Aminobutyric Acid–Related Genes in Postmortem Human Hippocampus in Schizophrenia and Bipolar Disorder

Abstract

IMPORTANCE Dysfunction related to γ-aminobutyric acid (GABA)-ergic neurotransmission in the pathophysiology of major psychosis has been well established by the work of multiple groups across several decades, including the widely replicated downregulation of GAD1. Prior gene expression and network analyses within the human hippocampus implicate a broader network of genes, termed the GAD1 regulatory network, in regulation of GAD1 expression. Several genes within this GAD1 regulatory network show diagnosis-and sector-specific expression changes within the circuitry of the hippocampus, influencing abnormal GAD1 expression in schizophrenia and bipolar disorder.OBJECTIVE To investigate the hypothesis that aberrant DNA methylation contributes to circuit-and diagnosis-specific abnormal expression of GAD1 regulatory network genes in psychotic illness. DESIGN, SETTING, AND PARTICIPANTSThis epigenetic association study targeting GAD1 regulatory network genes was conducted between July 1, 2012, and June 30, 2014. Postmortem human hippocampus tissue samples were obtained from 8 patients with schizophrenia, 8 patients with bipolar disorder, and 8 healthy control participants matched for age, sex, postmortem interval, and other potential confounds from the Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, Massachusetts. We extracted DNA from laser-microdissected stratum oriens tissue of cornu ammonis 2/3 (CA2/3) and CA1 postmortem human hippocampus, bisulfite modified it, and assessed it with the Infinium HumanMethylation450 BeadChip (Illumina, Inc). The subset of CpG loci associated with GAD1 regulatory network genes was analyzed in R version 3.1.0 software (R Foundation) using the minfi package. Findings were validated using bisulfite pyrosequencing. MAIN OUTCOMES AND MEASURESMethylation levels at 1308 GAD1 regulatory network-associated CpG loci were assessed both as individual sites to identify differentially methylated positions and by sharing information among colocalized probes to identify differentially methylated regions.RESULTS A total of 146 differentially methylated positions with a false detection rate lower than 0.05 were identified across all 6 groups (2 circuit locations in each of 3 diagnostic categories), and 54 differentially methylated regions with P < .01 were identified in single-group comparisons. Methylation changes were enriched in MSX1, CCND2, and DAXX at specific loci within the hippocampus of patients with schizophrenia and bipolar disorder.CONCLUSIONS AND RELEVANCE This work demonstrates diagnosis-and circuit-specific DNA methylation changes at a subset of GAD1 regulatory network genes in the human hippocampus in schizophrenia and bipolar disorder. These genes participate in chromatin regulation and cell cycle control, supporting the concept that the established GABAergic dysfunction in these disorders is related to disruption of GABAergic interneuron physiology at specific circuit locations within the human hippocampus.

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

“…Hippocampal GABA dysfunction has been implicated in schizophrenia and age-related cognitive decline (Lisman et al 2008;Huang and Mucke 2012;Stanley et al 2012;Heckers and Konradi 2014;Nava-Mesa et al 2014;Ruzicka et al 2015). Given the close link between neural activity and metabolic activation (Sokoloff 1981), the enhanced hippocampal mutli-unit activity caused by acute GABA antagonism is consistent with the hippocampal metabolic overactivity characterizing early stages of these disorders (Schobel et al 2009;Bakker et al 2012;Huang and Mucke 2012).…”

“…Hippocampal neural disinhibition has emerged as a key pathophysiological feature of schizophrenia, based on consistent findings of metabolic overactivity at rest and altered post-mortem markers of GABA function in the hippocampus of schizophrenia patients (Lisman et al 2008;Heckers and Konradi 2014;Ruzicka et al 2015). Hippocampal GABA dysfunction has also been implicated in other cognitive disorders, notably age-related cognitive decline, although the evidence is more preliminary than the evidence implicating GABA dysfunction in schizophrenia (Huang and Mucke 2012;Stanley et al 2012;Nava-Mesa et al 2014).…”

Genetic studies of alcohol dependence in the context of the addiction cycle

“…Indeed, MSX1 is expressed at higher levels in the adult hippocampus than in the fetal hippocampus (Ramos et al, 2004). In a genome-wide DNA methylation study examining hippocampal expression of GABA-related genes, MSX1 contained the greatest number of differentially methylated positions associated with schizophrenia and bipolar disorder (Ruzicka et al, 2015). In addition, MSX1 is differentially expressed in the striatum of rats that display a conditioned place preference for psychostimulants (Dela Pena et al, 2013).…”

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

“…MSX1 is a direct downstream target of DLX5 during early inner ear development [Sajan et al, 2011]. Methylation changes in MSX1 are found in the hippocampus of SZ patients as a part of the circuit-specific DNA methylation changes affecting the glutamate decarboxylase 1 regulatory network in SZ, which may explain the GABAergic dysfunctions in this condition [Ruzicka et al, 2015].…”