title: TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons.
abstract: TRPM4 is a calcium-activated but calcium-impermeable non-selective cation (CAN) channel. Previous studies have shown that TRPM4 is an important regulator of Ca(2+)-dependent changes in membrane potential in excitable and non-excitable cell types. However, its physiological significance in neurons of the central nervous system remained unclear. Here, we report that TRPM4 proteins form a CAN channel in CA1 neurons of the hippocampus and we show that TRPM4 is an essential co-activator of N-methyl-D-aspartate (NMDA) receptors (NMDAR) during the induction of long-term potentiation (LTP). Disrupting the Trpm4 gene in mice specifically eliminates NMDAR-dependent LTP, while basal synaptic transmission, short-term plasticity, and NMDAR-dependent long-term depression are unchanged. The induction of LTP in Trpm4 (-/-) neurons was rescued by facilitating NMDA receptor activation or post-synaptic membrane depolarization. Accordingly, we obtained normal LTP in Trpm4 (-/-) neurons in a pairing protocol, where post-synaptic depolarization was applied in parallel to pre-synaptic stimulation. Taken together, our data are consistent with a novel model of LTP induction in CA1 hippocampal neurons, in which TRPM4 is an essential player in a feed-forward loop that generates the post-synaptic membrane depolarization which is necessary to fully activate NMDA receptors during the induction of LTP but which is dispensable for the induction of long-term depression (LTD). These results have important implications for the understanding of the induction process of LTP and the development of nootropic medication.
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, bus 802, 3000, Leuven, Belgium.|TRP Research Platform Leuven (TRPLe), University of Leuven, 3000, Leuven, Belgium.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Menigoz
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Tiensestraat 102, 3000, Leuven, Belgium.|TRP Research Platform Leuven (TRPLe), University of Leuven, 3000, Leuven, Belgium.
authors.forename: Tariq
authors.initials: T
authors.lastname: Ahmed
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Tiensestraat 102, 3000, Leuven, Belgium.|TRP Research Platform Leuven (TRPLe), University of Leuven, 3000, Leuven, Belgium.
authors.forename: Victor
authors.initials: V
authors.lastname: Sabanov
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, bus 802, 3000, Leuven, Belgium.|TRP Research Platform Leuven (TRPLe), University of Leuven, 3000, Leuven, Belgium.
authors.forename: Koenraad
authors.initials: K
authors.lastname: Philippaert
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, bus 802, 3000, Leuven, Belgium.|TRP Research Platform Leuven (TRPLe), University of Leuven, 3000, Leuven, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, bus 802, 3000, Leuven, Belgium.|TRP Research Platform Leuven (TRPLe), University of Leuven, 3000, Leuven, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Kerselaers
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, bus 802, 3000, Leuven, Belgium.|TRP Research Platform Leuven (TRPLe), University of Leuven, 3000, Leuven, Belgium.
authors.forename: Andrei
authors.initials: A
authors.lastname: Segal
authors.affiliation: Pharmakologisches Institut, Universität Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, bus 802, 3000, Leuven, Belgium.|TRP Research Platform Leuven (TRPLe), University of Leuven, 3000, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, bus 802, 3000, Leuven, Belgium.|TRP Research Platform Leuven (TRPLe), University of Leuven, 3000, Leuven, Belgium.
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Herestraat 49, bus 802, 3000, Leuven, Belgium. rudi.vennekens@med.kuleuven.be.|TRP Research Platform Leuven (TRPLe), University of Leuven, 3000, Leuven, Belgium. rudi.vennekens@med.kuleuven.be.
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Tiensestraat 102, 3000, Leuven, Belgium.|TRP Research Platform Leuven (TRPLe), University of Leuven, 3000, Leuven, Belgium.
authors.forename: Detlef
authors.initials: D
authors.lastname: Balschun
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D025461:Feedback, Physiological; D017774:Long-Term Potentiation; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D055366:Synaptic Potentials; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D050053:TRPM Cation Channels; C476766:TRPM4 protein, mouse
keywords: Long term potentiation; Synaptic plasticity; Synaptic transmission; TRPM4; Transient receptor potential ion channels