Enhancing GluN2A-type NMDA receptors impairs long-term synaptic plasticity and learning and memory

被引：0
作者：
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
机构：
[1] Nanjing University,Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Department of Neurology, Drum Tower Hospital, Medical School
[2] Women’s Hospital of Nanjing Medical University,Department of Prenatal Diagnosis
[3] Nanjing Maternity and Child Health Care Hospital,Department of Anesthesiology, Pain and Perioperative Medicine
[4] First Affiliated Hospital of Zhengzhou University,State Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, Jiangsu Key Laboratory of Molecular Medicine
[5] Nanjing University,Department of Orthopaedics
[6] Luhe People’s Hospital Affiliated to Yangzhou University,State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology
[7] Chinese Academy of Sciences,Chemistry and Biomedicine Innovation Center
[8] Nanjing University,undefined
[9] Guangdong Institute of Intelligence Science and Technology,undefined
来源：
Molecular Psychiatry | 2022年 / 27卷
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摘要：
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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页码：3468 / 3478
页数：10
相关论文
共 246 条
[1]  
Traynelis SF(2010)Glutamate receptor ion channels: structure, regulation, and function Pharm Rev 62 405-96
[2]  
Wollmuth LP(2013)NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease Nat Rev Neurosci 14 383-400
[3]  
McBain CJ(2011)The NMDA receptor complex as a therapeutic target in epilepsy: a review Epilepsy Behav 22 617-40
[4]  
Menniti FS(2015)Ionotropic GABA and glutamate receptor mutations and human neurologic diseases Mol Pharm 88 203-17
[5]  
Vance KM(2013)GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction Nat Genet 45 1061-6
[6]  
Ogden KK(2011)Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia Transl Psychiatry 1 1073-6
[7]  
Paoletti P(2013)GRIN2A mutations cause epilepsy-aphasia spectrum disorders Nat Genet 45 1870-3
[8]  
Bellone C(2010)Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region Epilepsia. 51 992-9
[9]  
Zhou Q(2018)A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder Mov Disord 33 317-30.
[10]  
Ghasemi M(2017)Functional evaluation of a de novo GRIN2A mutation identified in a patient with profound global developmental delay and refractory epilepsy Mol Pharm 91 e00495-24
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