NMDA receptor hypofunction for schizophrenia revisited: Perspectives from epigenetic mechanisms

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, t...

Full description

Saved in:
Bibliographic Details
Published in:Schizophrenia research 2020-03, Vol.217, p.60-70
Main Authors: Snyder, Melissa A., Gao, Wen-Jun
Format: Article
Language:English
Subjects:
Development
Dopamine
Epigenesis, Genetic
Epigenetics
Humans
Neuronal Plasticity
NMDA receptor hypofunction
Prefrontal cortex
Receptors, N-Methyl-D-Aspartate - genetics
Receptors, N-Methyl-D-Aspartate - metabolism
Schizophrenia
Schizophrenia - genetics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0920-9964
1573-2509
DOI:10.1016/j.schres.2019.03.010