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Metabotropic action of postsynaptic kainate receptors triggers hippocampal long-term potentiation

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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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Figure 1: KA increases AMPAR surface expression.
Figure 2: KAR activation induces LTP.
Figure 3: KAR LTP induces structural plasticity.
Figure 4: KAR LTP recruits Rab11-recycling endosomes to spines.
Figure 5: KAR LTP requires intracellular calcium increase, as well as PKC and PLC activation.
Figure 6: KAR LTP requires KAR metabotropic signaling.
Figure 7: KAR LTP does not require ionotropic KAR activation.

Change history

  • 08 March 2017

    In the version of this article initially published online, the graph in the second row of Figure 5c was a duplicate of the one in the first row. Also, "EPSC amplitudes" in the legend to Figure 5d should have read "EPSP slopes." Finally, the units on the x axes in Figure 4c, 5c, 6f and 7d should have been μm, not mm. The errors have been corrected in the print, PDF and HTML versions of this article.


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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.

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I.M.G.-G. designed and performed the biochemistry and imaging experiments and participated in electrophysiological experiments; M.M.P. designed and performed agonist- and stimulation-evoked electrophysiology and participated in imaging experiments. S.V.d.S. performed electrophysiology in wild-type and mice hippocampal slices; C.M. provided knockout mice and extensive advice; J.P.C. performed the MK-801, D-APV and CNQX dual pathway electrophysiological experiments. L.V. provided facilities and reagents and helped analyses the electrophysiological data. J.M.H. instigated the study and provided overall supervision and management. J.M.H., M.I.G.-G. and M.M.P. designed the study, analyzed the data and wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Milos M Petrovic, Inmaculada M González-González or Jeremy M Henley.

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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).

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