Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression

Abstract

Compelling evidence suggests that major depression is associated with dysfunction of the brain glutamatergic transmission, and that the glutamatergic N-methyl-d-aspartate (NMDA) receptor plays a role in antidepressant activity. Recent post-mortem studies demonstrate that depression is associated with altered concentrations of proteins associated with NMDA receptor signalling in the brain. The present study investigated glutamate signalling proteins in the amygdala from depressed subjects, given strong evidence for amygdala pathology in depression. Lateral amygdala samples were obtained from 13-14 pairs of age- sex-, and post-mortem-interval-matched depressed and psychiatrically healthy control subjects. Concentrations of NR1 and NR2A subunits of the NMDA receptor, as well as NMDA receptor-associated proteins such as post-synaptic density protein-95 (PSD-95) and neuronal nitric oxide synthase (nNOS) were measured by Western immunoblotting. Additionally, levels of enzymes involved in glutamate metabolism, including glutamine synthetase and glutamic acid decarboxylase (GAD-67), were measured in the same amygdala samples. NR2A protein levels were markedly and significantly elevated (+115%, p=0.03) in depressed subjects compared to controls. Interestingly, PSD-95 levels were also highly elevated (+128%, p=0.01) in the same depressed subjects relative to controls. Amounts of NR1, nNOS, glutamine synthetase, and GAD-67 were unchanged. Increased levels of NR2A and PSD-95 suggest that glutamate signalling at the NMDA receptor in the amygdala is disrupted in depression.

Epigenetics of the Depressed Brain: Role of Histone Acetylation and Methylation

“…Adding complication to molecular approaches in treating depression is that molecular adaptations do not occur globally but are often region-and cell type-specific. For example, in contrast to what has been observed in the PFC, NR2A, and PSD-95 are both increased in the amygdala of depressed humans (Karolewicz et al, 2009).…”

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

“…This suggests that the observed hypermethylation of the GRIN2A gene body may lead to overexpression of NR2A [19]. Consistent with this, elevated expression of NR2A has indeed been documented in the amygdala and locus coeruleus (LC) of MDD patients, but not in the hippocampus or PFC, which may have methodological reasons [20][21][22][23]. Notwithstanding these discrepancies, different combinations of specific NR2 subunits are known to result in NMDA receptors with different functional characteristics [22].…”

Aldosterone Signals the Onset of Depressive Behaviour in a Female Rat Model of Depression along with SSRI Treatment Resistance

“…Indeed, modulation of NMDA receptors and glutamatergic neurotransmission has recently been discussed as a possible new target area for treatment-refractory depression [54]. Interestingly, reduced brain Mg 2+ has been reported in SSRI-resistant depressed patients [55], and significantly higher levels of the NR2A sub-unit of NMDA receptors were observed in postmortem brains of depressed patients as compared to those of healthy controls [56]. Another finding reported for patients with treatment-resistant depression was a higher serum ghrelin concentration as compared to that in responders [25].…”