Long-term potentiation (LTP) in the rat hippocampus is the most extensively studied cellular model for learning and memory. Induction of classical LTP involves an NMDA-receptor- and calcium-dependent increase in functional synaptic AMPA receptors, mediated by enhanced recycling of internalized AMPA receptors back to the postsynaptic membrane. Here we report a physiologically relevant NMDA-receptor-independent mechanism that drives increased AMPA receptor recycling and LTP. This pathway requires the metabotropic action of kainate receptors and activation of G protein, protein kinase C and phospholipase C. Like classical LTP, kainate-receptor-dependent LTP recruits recycling endosomes to spines, enhances synaptic recycling of AMPA receptors to increase their surface expression and elicits structural changes in spines, including increased growth and maturation. These data reveal a new and, to our knowledge, previously unsuspected role for postsynaptic kainate receptors in the induction of functional and structural plasticity in the hippocampus.
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We are grateful to P. Rubin and N. Grosjean for excellent technical support, A. Singh for his help in some follow-up experiments, M. Gajic for the advice about statistics and J. Esteban (CBMSO, Madrid) for providing Rab constructs. We are grateful for financial support from the ERC (Proposal no. 232881), MRC (MR/L003791), BHF (PG/14/60/31014) and BBSRC (BB/K014366 and BB/K014358) to J.M.H.; EMBO Fellowships to I.M.G.-G. (ALTF 224-2009 and ASTF 438-2011) and M.M.P. (ASTF 232-2011); a grant from MRC (MR/M023729/1) to M.M.P.; grants from the Centre National de la Recherche Scientifique, the Conseil Régional d'Aquitaine, the Labex BRAIN and the Fundacao para a Ciencia e a Tecnologia to C.M. and S.V.d.S.; support from the Czech Science Foundation (GACR): 17-02300S) and Research Project of the AS CR RVO (67985823) to L.V.; and a grant from the Department of Science and Technology (DST) – Young Scientist Scheme (SERB/LS-779/2013) to J.P.C.
The authors declare no competing financial interests.
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Petrovic, M., Viana da Silva, S., Clement, J. et al. Metabotropic action of postsynaptic kainate receptors triggers hippocampal long-term potentiation. Nat Neurosci 20, 529–539 (2017). https://doi.org/10.1038/nn.4505
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