TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons

Aurélie Menigoz, Tariq Ahmed, Victor Sabanov, Koenraad Philippaert, Silvia Pinto, Sara Kerselaers, Andrei Segal, Marc Freichel, Thomas Voets, Bernd Nilius, Rudi Vennekens, Detlef Balschun

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6 Citations (Scopus)

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 Ca2+-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.

Original languageEnglish
Pages (from-to)593-607
Number of pages15
JournalPflugers Archiv European Journal of Physiology
Volume468
Issue number4
DOIs
Publication statusPublished - 1 Apr 2016
Externally publishedYes

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Keywords

  • Long term potentiation
  • Synaptic plasticity
  • Synaptic transmission
  • Transient receptor potential ion channels
  • TRPM4

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

Cite this

Menigoz, A., Ahmed, T., Sabanov, V., Philippaert, K., Pinto, S., Kerselaers, S., Segal, A., Freichel, M., Voets, T., Nilius, B., Vennekens, R., & Balschun, D. (2016). TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons. Pflugers Archiv European Journal of Physiology, 468(4), 593-607. https://doi.org/10.1007/s00424-015-1764-7