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

Research output: Contribution to journalArticle

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

Fingerprint

Long-Term Potentiation
Depolarization
Neurons
N-Methyl-D-Aspartate Receptors
Membranes
Synaptic Membranes
Cations
Nootropic Agents
Calcium
Neurology
Plasticity
Genes
Chemical activation
aspartic acid receptor
Synaptic Transmission
Membrane Potentials
Hippocampus
Central Nervous System
Proteins

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

TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons. / Menigoz, Aurélie; Ahmed, Tariq; Sabanov, Victor; Philippaert, Koenraad; Pinto, Silvia; Kerselaers, Sara; Segal, Andrei; Freichel, Marc; Voets, Thomas; Nilius, Bernd; Vennekens, Rudi; Balschun, Detlef.

In: Pflugers Archiv European Journal of Physiology, Vol. 468, No. 4, 01.04.2016, p. 593-607.

Research output: Contribution to journalArticle

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, vol. 468, no. 4, pp. 593-607. https://doi.org/10.1007/s00424-015-1764-7
Menigoz, Aurélie ; Ahmed, Tariq ; Sabanov, Victor ; Philippaert, Koenraad ; Pinto, Silvia ; Kerselaers, Sara ; Segal, Andrei ; Freichel, Marc ; Voets, Thomas ; Nilius, Bernd ; Vennekens, Rudi ; Balschun, Detlef. / TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons. In: Pflugers Archiv European Journal of Physiology. 2016 ; Vol. 468, No. 4. pp. 593-607.
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AU - Menigoz, Aurélie

AU - Ahmed, Tariq

AU - Sabanov, Victor

AU - Philippaert, Koenraad

AU - Pinto, Silvia

AU - Kerselaers, Sara

AU - Segal, Andrei

AU - Freichel, Marc

AU - Voets, Thomas

AU - Nilius, Bernd

AU - Vennekens, Rudi

AU - Balschun, Detlef

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AB - 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.

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