The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning

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Long-term potentiation (LTP) and depression (LTD) at glutamatergic synapses are intensively investigated processes for understanding the synaptic basis for learning and memory, but the underlying molecular mechanisms remain poorly understood. We have made three mouse lines where the C-terminal domains (CTDs) of endogenous AMPA receptors (AMPARs), the principal mediators of fast excitatory synaptic transmission, are specifically exchanged. These mice display profound deficits in synaptic plasticity without any effects on basal synaptic transmission. Our study reveals that the CTDs of GluA1 and GluA2, the key subunits of AMPARs, are necessary and sufficient to drive NMDA receptor–dependent LTP and LTD, respectively. In addition, these domains exert differential effects on spatial and contextual learning and memory. These results establish dominant roles of AMPARs in governing bidirectional synaptic and behavioral plasticity in the CNS.

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We thank Y.-T. Wang for GluA2-CTD antibodies, W. Lu for the use of the fear conditioning chambers, and L. Han, R. Mao and other members of Jia laboratory for technical assistance and comments on the manuscript. This work was supported by grants from the Canadian Institutes of Health Research (CIHR, MOP119421, Z.J.; FDN154276, G.L.C.), Canadian Natural Science and Engineering Research Council (NSERC, RGPIN341498, Z.J.), Natural Science Foundation of China (NSFC 31571040, Z.Z.), NSFC and CIHR Joint Health Research Initiative Program (81161120543, W.X. and CCI117959, Z.J.), Brain Canada (Z.J. and G.L.C.) and the Hospital for Sick Children Foundation (Z.J.). S.X. was supported by the Scientific Research Foundation of Graduate School of Southeast University, China.

Author information

Author notes

  1. Zikai Zhou, An Liu, Shuting Xia and Celeste Leung contributed equally to this work.


  1. Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada

    • Zikai Zhou
    • , Shuting Xia
    • , Celeste Leung
    • , Yanghong Meng
    •  & Zhengping Jia
  2. Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    • Zikai Zhou
    • , Shuting Xia
    • , Celeste Leung
    • , Yanghong Meng
    • , Pojeong Park
    • , Graham L. Collingridge
    •  & Zhengping Jia
  3. The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China

    • Zikai Zhou
    • , An Liu
    • , Shuting Xia
    • , Junxia Qi
    •  & Wei Xie
  4. Co-innovation Center of Neuroregeneration, Nantong University, Nanjing, China

    • Zikai Zhou
    •  & Wei Xie
  5. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    • Pojeong Park
    •  & Graham L. Collingridge
  6. Centre for Synaptic Plasticity, Department of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UK

    • Pojeong Park
    •  & Graham L. Collingridge


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Z.J. conceived and supervised the study. A.L., Z.Z., G.L.C. and Z.J. designed the experiments. Z.Z., A.L., S.X., C.L., J.Q. and Y.M. performed experiments. Z.Z., A.L., S.X., C.L., P.P. and W.X. analyzed data. Z.J., G.L.C. and A.L. wrote the paper. All authors read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Graham L. Collingridge or Zhengping Jia.

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