NMDA receptor hypofunction for schizophrenia revisited: Perspectives from epigenetic mechanisms

Abstract

Schizophrenia (SZ) is a neurodevelopmental disorder with cognitive deficits manifesting during early stages of the disease. Evidence suggests that genetic factors in combination with environmental insults lead to complex changes to glutamatergic, GABAergic, and dopaminergic systems. In particular, the N-methyl-D-aspartate receptor (NMDAR), a major glutamate receptor subtype, is implicated in both the disease progression and symptoms of SZ. NMDARs are critical for synaptic plasticity and cortical maturation, as well as learning and memory processes. In fact, any deviation from normal NMDAR expression and function can have devastating consequences. Surprisingly, there is little evidence from human patients that direct mutations of NMDAR genes contribute to SZ. One intriguing hypothesis is that epigenetic changes, which could result from early insults, alter protein expression and contribute to the NMDAR hypofunction found in SZ. Epigenetics is referred to as modifications that alter gene transcription without changing the DNA sequence itself. In this review, we first discuss how epigenetic changes to NMDAR genes could contribute to NMDAR hypofunction. We then explore how NMDAR hypofunction may contribute to epigenetic changes in other proteins or genes that lead to synaptic dysfunction and symptoms in SZ. We argue that NMDAR hypofunction occurs in early stage of the disease, and it may consequentially initiate GABA and dopamine deficits. Therefore, targeting NMDAR dysfunction during the early stages would be a promising avenue for prevention and therapeutic intervention of cognitive and social deficits that remain untreatable. Finally, we discuss potential questions regarding the epigenetic of SZ and future directions for research.

Frontal–striatal connectivity and positive symptoms of schizophrenia: implications for the mechanistic basis of prefrontal rTMS

“…This framework provides a mechanistic explanation as to why those rTMS protocols that cause disinhibition (e.g., > 5-10 Hz) may worsen positive symptoms. While this conjecture is based on the glutamate hypothesis [4,25,32,41,42], our data neither supports nor refutes the primacy of glutamate over dopaminergic dysfunction in psychosis.…”

Is Memantine Effective as an NMDA Receptor Antagonist in Adjunctive Therapy for Schizophrenia?

“…However, MK-801 was not fully studied for human use, because it produced significant mental side effects during its early clinical trials as an anticonvulsant, and it appeared to have the same psychotomimetic properties as PCP in humans based on behavioral studies using a variety of species, including rhesus monkeys [ 12 ]. Thus, it was proposed that schizophrenia could result from hypofunction of NMDA receptors [ 13 , 14 , 15 ]. The chemical structures of memantine and other NMDA receptor antagonists are represented in Figure 1 .…”

Pediatric Anti-NMDAR Encephalitis in Southern China: Analysis of 107 Cases

“…Extrasynaptic NMDAR is more commonly in GluN1/2B, while synaptic NMDAR is more commonly in GluN1/2A [6]. And during development from juvenile to adult, NMDAR subunit switch from GluN2B to GluN2A [22]. In future, more researches about the NMDAR function network in physiology, disease during development need to do in order to elucidate the pathological mechanism of anti-NMDAR encephalitis.…”

“…Prodromal events could play an important role in epigenetic change in patients. For now, epigenetic mechanisms for NMDAR receptor hypofunction in schizophrenia provided new insights into understanding of its neuropathophysiology and early interventions [22].…”