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

Jihoon Jo; Gi Hoon Son; Bryony L. Winters; Myung Jong Kim; Daniel J. Whitcomb; Bryony A. Dickinson; Youn Bok Lee; Kensuke Futai; Mascia Amici; Morgan Sheng; Graham L. Collingridge; Kwangwook Cho

doi:10.1038/nn.2636

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

Jihoon Jo, Gi Hoon Son, Bryony L. Winters, Myung Jong Kim, Daniel J. Whitcomb, Bryony A. Dickinson, Youn Bok Lee, Kensuke Futai, Mascia Amici, Morgan Sheng, Graham L. Collingridge, Kwangwook Cho

Research output: Contribution to journal › Article › peer-review

78 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1216-1224
Number of pages	9
Journal	Nature Neuroscience
Volume	13
Issue number	10
DOIs	https://doi.org/10.1038/nn.2636
Publication status	Published - 2010 Oct
Externally published	Yes

ASJC Scopus subject areas

Neuroscience(all)

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Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95. / Jo, Jihoon; Son, Gi Hoon; Winters, Bryony L.; Kim, Myung Jong; Whitcomb, Daniel J.; Dickinson, Bryony A.; Lee, Youn Bok; Futai, Kensuke; Amici, Mascia; Sheng, Morgan; Collingridge, Graham L.; Cho, Kwangwook.

In: Nature Neuroscience, Vol. 13, No. 10, 10.2010, p. 1216-1224.

Research output: Contribution to journal › Article › peer-review

Jo, Jihoon ; Son, Gi Hoon ; Winters, Bryony L. ; Kim, Myung Jong ; Whitcomb, Daniel J. ; Dickinson, Bryony A. ; Lee, Youn Bok ; Futai, Kensuke ; Amici, Mascia ; Sheng, Morgan ; Collingridge, Graham L. ; Cho, Kwangwook. / Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95. In: Nature Neuroscience. 2010 ; Vol. 13, No. 10. pp. 1216-1224.

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

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.",

author = "Jihoon Jo and Son, {Gi Hoon} and Winters, {Bryony L.} and Kim, {Myung Jong} and Whitcomb, {Daniel J.} and Dickinson, {Bryony A.} and Lee, {Youn Bok} and Kensuke Futai and Mascia Amici and Morgan Sheng and Collingridge, {Graham L.} and Kwangwook Cho",

note = "Funding Information: This work was funded by the Biotechnology and Biological Sciences Research Council (K.C.), the Medical Research Council (G.L.C.), UK Alzheimer{\textquoteright}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.).",

year = "2010",

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doi = "10.1038/nn.2636",

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AU - Jo, Jihoon

AU - Son, Gi Hoon

AU - Winters, Bryony L.

AU - Kim, Myung Jong

AU - Whitcomb, Daniel J.

AU - Dickinson, Bryony A.

AU - Lee, Youn Bok

AU - Futai, Kensuke

AU - Amici, Mascia

AU - Sheng, Morgan

AU - Collingridge, Graham L.

AU - Cho, Kwangwook

N1 - Funding Information: 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.).

PY - 2010/10

Y1 - 2010/10

N2 - 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.

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

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