Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression

Abstract

Recent neuroimaging and postmortem studies have demonstrated abnormalities in glutamatergic transmission in major depression. Glutamate NMDA (N-methyl-D-aspartate) receptors are one of the major mediators of excitatory neurotransmission in the central nervous system. At synaptic sites, NMDA receptors are linked with postsynaptic density protein-95 (PSD-95) that plays a key role in mediating trafficking, clustering, and downstream signaling events, following receptor activation. In this study, we examined the expression of NMDA receptor subunits NR1, NR2A, and NR2B as well as PSD-95 in the anterior prefrontal cortex (PFC) using Western blot method. Cortical samples were obtained from age, gender and postmortem interval matched depressed and psychiatrically healthy controls. The results revealed that there was a reduced expression of the NMDA receptor subunits NR2A (−54%) and NR2B (−48%), and PSD-95 protein level (−40%) in the PFC of depressed subjects relative to controls, with no change in the NR1 subunit. The alterations in NMDA receptor subunits, especially the NR2A and NR2B, as well as PSD-95 suggest an abnormality in the NMDA receptor signaling in the PFC in major depression. Our findings in conjunction with recent clinical, cellular, and neuroimaging studies further implicate the involvement of glutamate neurotransmission in the pathophysiology of depression. This study provides additional evidence that NMDA receptor complex is a target for discovery of novel antidepressants.

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].…”

Too Much of a Good Thing: Blocking Noradrenergic Facilitation in Medial Prefrontal Cortex Prevents the Detrimental Effects of Chronic Stress on Cognition

“…As discussed above, elevating NE may enhance ED performance by facilitating glutamate signaling in the mPFC. Depression has been associated with hypoactivity, reduced glutamate levels, and decreased NMDA receptor expression in the mPFC (Hasler et al, 2007;Feyissa et al, 2009;Merkl et al, 2011). Chronic stress has been shown to impair limbic-prefrontal cortical function by downregulating NMDA receptor expression in the mPFC of rats (Lee and Goto, 2011).…”

Major Depresif Bozukluk’ Tanımı, Etyolojisi ve Epidemiyolojisi: Bir Gözden Geçirme

“…Hayvan deneylerinde glutamaterjik sistemde stresle ilişkili değişiklikler gözlenmesi ve bunun nöron kaybı (eksitotoksisite) ile ilişkisi, depresyonlu hastalarda glutamaterjik sistem bozukluklarının gös-terilmesi, antidepresan (aAd) ve duygudurum dengeleyici (DDD) ilaçların glutamaterjik etkileri, depresyon tedavisinde glutamatı etkileyen ajanların etkinliği, tedaviye direçli bazı MDB hastalarına verilen tek doz NMDA reseptör antagonisti olan ketaminin hızlı ve geniş bir antidepresan etki oluşturması, glutamat salınımını engelleyen ilaçların (lamotrijin, riluzol, lityum vb.) Ad özellikler sergilemesi, depresyon hastalarında MR spektroskopi ile anormal glutamat düzeyleri saptanması, kadavra doku örneklerinde anormal NMDA uyarılarının olduğuna dair kanıtlar bulunması gibi sonuçlar glutamatın depresyon etyolojisindeki yerine yönelik kanıtlar sunar (46)(47)(48)(49). Sonuç olarak SSS'deki yaygınlığı ve nöronal hasara yol açma potansiyeli göz önüne alındığında glutamat ve NMDA reseptörleri, sinaptik plastisitede kayıp ve hipokampal atrofiye neden olabilen bir hastalık olan MDB'nin etiyopatogenezi ve tedavisi açısından ilgiyi hak eder .…”