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Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

Nature Neuroscience volume 13, pages 1216–1224 (2010)Cite this article

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Abstract

Although muscarinic acetylcholine receptors (mAChRs) and NMDA receptors (NMDARs) are important for synaptic plasticity, learning and memory, the manner in which they interact is poorly understood. We found that stimulation of muscarinic receptors, either by an agonist or by the synaptic release of acetylcholine, led to long-term depression (LTD) of NMDAR-mediated synaptic transmission. This form of LTD involved the release of Ca2+ from IP3-sensitive intracellular stores and was expressed via the internalization of NMDARs. Our results suggest that the molecular mechanism involves a dynamic interaction between the neuronal calcium sensor protein hippocalcin, the clathrin adaptor molecule AP2, the postsynaptic density enriched protein PSD-95 and NMDARs. We propose that hippocalcin binds to the SH3 region of PSD-95 under basal conditions, but it translocates to the plasma membrane on sensing Ca2+; in doing so, it causes PSD-95 to dissociate from NMDARs, permitting AP2 to bind and initiate their dynamin-dependent endocytosis.

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Figure 1: Activation of muscarinic receptors induces LTD of NMDAR-mediated synaptic transmission.
Figure 2: The synaptic activation of muscarinic receptors induces LTDN.
Figure 3: Hippocalcin is required for mAChR-LTDN.
Figure 4: Hip-RNAi blocks CCh-LTDN.
Figure 5: mAChR-LTDN involves the internalization of NMDARs.
Figure 6: Dynamic interactions between NMDARs, hippocalcin, AP2 and PSD-95.
Figure 7: Hippocalcin interacts with PSD-95.
Figure 8: The SH3 domain of PSD-95 is involved in CCh-LTDN.

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Acknowledgements

This work was funded by the Biotechnology and Biological Sciences Research Council (K.C.), the Medical Research Council (G.L.C.), UK Alzheimer's Research Trust (K.C. and D.W.), The Royal Society (J.J.) and Brain Research Centre of the 21st Century Frontier Research Programme, funded by the Korean Ministry of Education and Science and Technology (K.C. and G.L.C.).

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Author notes

  1. Jihoon Jo and Gi Hoon Son: These authors contributed equally to this work.

Authors and Affiliations

  1. Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Faculty of Medicine and Dentistry, University of Bristol, Bristol, UK

    Jihoon Jo, Gi Hoon Son, Bryony L Winters, Daniel J Whitcomb, Bryony A Dickinson, Youn-Bok Lee & Kwangwook Cho

  2. MRC Centre for Synaptic Plasticity, University of Bristol, Bristol, UK

    Bryony L Winters, Mascia Amici, Graham L Collingridge & Kwangwook Cho

  3. The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Myung Jong Kim, Kensuke Futai & Morgan Sheng

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Contributions

The study was conceived by K.C., and the experiments were designed by K.C., M.S. and G.L.C. The experiments were carried out by J.J., G.H.S., B.L.W., M.J.K., D.J.W., B.A.D., Y.-B.L., K.F. and M.A., and the manuscript was written by G.L.C., M.S. and K.C.

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Correspondence to Kwangwook Cho.

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Jo, J., Son, G., Winters, B. et al. Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95. Nat Neurosci 13, 1216–1224 (2010). https://doi.org/10.1038/nn.2636

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