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

Kwangwook Cho (1) , Jihoon Jo (1) , Gi Hoon Son (1) , Bryony Laura Winters (1) , Myungjong Kim (1) , Daniel Whitcomb (1) , Bryony Dickinson (1) , Youn-Bok Lee (1) , Kensuke Futai (1) , Mascia Amici (1) , Morgan Sheng (1) , Graham L Collingridge (1)

1 Henry Wellcome LINE & MRC Centre for Synaptic Plasticity

Although muscarinic acetylcholine receptors (mAChRs) and N-methyl-D-aspartate receptors (NMDARs) are of critical importance in synaptic plasticity, learning and memory, how they interact is poorly understood. We show that stimulation of muscarinic receptors, either by an agonist or by the synaptic release of acetylcholine, leads to long-term depression (LTD) of NMDAR-mediated synaptic transmission. This novel form of LTD involves the release of Ca2+ from IP3-sensitive intracellular stores and is expressed via the internalisation of NMDARs. We present evidence 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 under basal conditions hippocalcin binds to the SH3 region of PSD-95 but on sensing Ca2+ it translocates to the plasma membrane; in doing so it causes PSD-95 to dissociate from NMDARs so permitting AP2 to bind and initiate their dynamin-dependent endocytosis.

Mots clés: Plasticity; Synaptic Transmission; Neurophysiology

Kwangwook Cho, Jihoon Jo, Gi Hoon Son, Bryony Laura Winters, Myungjong Kim, et al.. Muscarinic receptors induce LTD of NMDAR-EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95. Nature Neuroscience, 2010, 13 (10), pp.1216. ⟨10.1038/nn.2636⟩. ⟨hal-00578277⟩