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

Molecular Psychiatry volume 27, pages 3468–3478 (2022)Cite this article

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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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Fig. 1: Pedigree and identification of the GluN2A_K879R variant.
Fig. 2: The K879R variant enhances the surface expression of NMDARs by disrupting ER retention.
Fig. 3: Overexpression of GluN2A_K879R enhances NMDAR-EPSCs.
Fig. 4: GluN2A_K879R KI mice show impaired learning and memory capacities.
Fig. 5: The expression of glutamate receptor proteins in KI mice.
Fig. 6: GluN2A_K879R KI alters synaptic transmission and plasticity.

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Acknowledgements

This work is supported by grants from the National Key R&D Program of China (2019YFA0801603 to YSS), the National Natural Science Foundation of China (32170951 and 91849112 to YSS, 81901161 to JC, 81770236 to ZFX, 81971398 to PH and 31871032 to NS), Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB17 to NS), the Fundamental Research Funds for the Central Universities (0903-14380029 to YSS), the Natural Science Foundation of Jiangsu Province (BE2019707 to YSS and BK20181121 to PH), Special Fund for Science and Technology Innovation Strategy of Guangdong Province (2021B0909050004 to YSS) and Yunnan Applied Basic Research Projects (2019FA008 and 2019FJ003 to NS).

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Author notes

  1. These authors contributed equally: Qing-Qing Li, Jiang Chen, Ping Hu.

Authors and Affiliations

  1. Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Department of Neurology, Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210032, China

    Qing-Qing Li, Jiang Chen, Jia-Hui Sun, Yan-Yu Zang, Guiquan Chen, Yun Xu & Yun Stone Shi

  2. Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, China

    Ping Hu, Hao-Yang Feng, Feng-Chang Qiao & Zhengfeng Xu

  3. Department of Anesthesiology, Pain and Perioperative Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Min Jia & Jian-Jun Yang

  4. State Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210032, China

    Jia-Hui Sun, Yan-Yu Zang, Guiquan Chen, Yun Xu & Yun Stone Shi

  5. Department of Orthopaedics, Luhe People’s Hospital Affiliated to Yangzhou University, Nanjing, 211500, China

    Yong-Yun Shi

  6. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China

    Nengyin Sheng

  7. Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, 210032, China

    Yun Stone Shi

  8. Guangdong Institute of Intelligence Science and Technology, Zhuhai, 519031, China

    Yun Stone Shi

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  1. Qing-Qing Li
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Contributions

Q-QL, JC and J-HS carried out electrophysiological analysis. Q-QL, MJ, H-YF and GC analyzed surface expression. PH, F-CQ and ZX collected the clinical information. Y-YZ and Y-YS designed the KI mice. NS, J-JY and YSS designed the experiments. YX supervised the study. YSS wrote the paper.

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Correspondence to Jian-Jun Yang, Zhengfeng Xu or Yun Stone Shi.

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Li, QQ., Chen, J., Hu, P. et al. Enhancing GluN2A-type NMDA receptors impairs long-term synaptic plasticity and learning and memory. Mol Psychiatry 27, 3468–3478 (2022). https://doi.org/10.1038/s41380-022-01579-7

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