Enhancing GluN2A-type NMDA Receptors Impairs Long-term Synaptic Plasticity and Learning and Memory

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2022 Apr 28

PMID 35484243

Authors

Qing-Qing Li

Jiang Chen

Ping Hu

Min Jia

Jia-Hui Sun

Hao-Yang Feng

Feng-Chang Qiao

Yan-Yu Zang

Yong-Yun Shi

Guiquan Chen

Nengyin Sheng

Yun Xu

Jian-Jun Yang

Zhengfeng Xu

Yun Stone Shi

Affiliations

Soon will be listed here.

Abstract

N-methyl-D-aspartic acid type glutamate receptors (NMDARs) play critical roles in synaptic transmission and plasticity, the dysregulation of which leads to cognitive defects. Here, we identified a rare variant in the NMDAR subunit GluN2A (K879R) in a patient with intellectual disability. The K879R mutation enhanced receptor expression on the cell surface by disrupting a KKK motif that we demonstrated to be an endoplasmic reticulum retention signal. Expression of GluN2A_K879R in mouse hippocampal CA1 neurons enhanced the excitatory postsynaptic currents mediated by GluN2A-NMDAR but suppressed those mediated by GluN2B-NMDAR and the AMPA receptor. GluN2A_K879R knock-in mice showed similar defects in synaptic transmission and exhibited impaired learning and memory. Furthermore, both LTP and LTD were severely impaired in the KI mice, likely explaining their learning and memory defects. Therefore, our study reveals a new mechanism by which elevated synaptic GluN2A-NMDAR impairs long-term synaptic plasticity as well as learning and memory.

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