TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons.
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.
['Menigoz|Aurélie|A|', 'Ahmed|Tariq|T|', 'Sabanov|Victor|V|', 'Philippaert|Koenraad|K|', 'Pinto|Silvia|S|', 'Kerselaers|Sara|S|', 'Segal|Andrei|A|', 'Freichel|Marc|M|', 'Voets|Thomas|T|', 'Nilius|Bernd|B|', 'Vennekens|Rudi|R|', 'Balschun|Detlef|D|']
D000818:Animals D056547:CA1 Region, Hippocampal D002478:Cells, Cultured D025461:Feedback, Physiological D017774:Long-Term Potentiation D051379:Mice D009474:Neurons D016194:Receptors, N-Methyl-D-Aspartate D055366:Synaptic Potentials D050053:TRPM Cation Channels
TRPM4 Synaptic transmission Long term potentiation Synaptic plasticity Transient receptor potential ion channels