Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression

Abstract

Current perspectives on the molecular underpinnings of major depressive disorder (MDD) posit a mechanistic role of epigenetic DNA modifications in mediating the interaction between environmental risk factors and a genetic predisposition. However, conclusive evidence for differential methylation signatures in the brain's epigenome of MDD patients as compared to controls is still lacking. To address this issue, we conducted a pilot study including an epigenome-wide methylation analysis in six individuals diagnosed with recurrent MDD and six control subjects matched for age and gender, with a priori focus on the hippocampus and prefrontal cortex as pathophysiologically relevant candidate regions. Our analysis revealed differential methylation profiles of 11 genes in hippocampus and 20 genes in prefrontal cortex, five of which were selected for replication of the methylation status using pyrosequencing. Among these replicated targets, GRIN2A was found to be hypermethylated in both prefrontal cortex and hippocampus. This finding may be of particular functional relevance as GRIN2A encodes the glutamatergic N-methyl-D-aspartate receptor subunit epsilon-1 (NR2A) and is known to be involved in a plethora of synaptic plasticity-related regulatory processes probably disturbed in MDD.

The Transition from Acute to Chronic Pain: Dynamic Epigenetic Reprogramming of the Mouse Prefrontal Cortex up to One Year Following Nerve Injury

“…The average magnitude of differential methylation between Sham and SNI is approximately 25-30% at all time points. This is a robust shift in methylation state for most DM CpG positions and is on par with that observed in the brain for major depressive disorder [32].…”

DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: a prospective analysis

“…Researchers have taken diverse approaches in examining patterns of DNAm that are associated with major depression; perhaps, not surprisingly, a wide range of findings have been reported. Most studies have found that the the CpG sites (using candidate and epigenome-wide approaches) associated with concurrent depressive symptoms or diagnosis [43][44][45][46][47] were characterized by lower levels of methylation (c.f., ref. 58 ).…”

“…We assessed and followed the girls prospectively into adulthood, or until they experienced their first depressive episode. Although some recent research has found no methylation sites that survived correction in relation to MDD 42 , several prior studies reported concurrent depressive symptoms and diagnoses were associated with DNAm using various approaches [43][44][45][46][47] . Given the biological relevance of HPA-axis function to risk for MDD, and that epigenetic variation may reflect combined genetic and environmental risks, we hypothesized that DNAm in CpG sites in HPA-axis genes assessed in early adolescence would predict the onset of MDD.…”

Modulation of catalase, copper and zinc in the hippocampus and the prefrontal cortex in social isolation-induced depression in male rats

“…The hippocampus and prefrontal cortex have been previously linked to emotions and emotional disturbances (Webster et al, 2001;Jin and Maren, 2015). Mechanisms underlying depression based on previous studies include methylation of NMDA receptors in prefrontal cortex and hippocampus (Kaut et al, 2015). In another study, the effectiveness of olanzapine in treatment-resistant depression has been attributed to cellular proliferation in the hippocampus and prefrontal cortex (Kodama et al, 2004).…”