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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 Ca2+-dependent changes in membrane potential in excitable and non-excitable cell types. However, its physiological significance in neurons of t...

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Main Authors: Menigoz, Aurélie (Author) , Ahmed, Tariq (Author) , Sabanov, Victor (Author) , Philippaert, Koenraad (Author) , Pinto, Silvia (Author) , Kerselaers, Sara (Author) , Segal, Andrei (Author) , Freichel, Marc (Author) , Voets, Thomas (Author) , Nilius, Bernd (Author) , Vennekens, Rudi (Author) , Balschun, Detlef (Author)
Format: Article (Journal)
Language:English
Published: 2016
In: Pflügers Archiv
Year: 2015, Volume: 468, Issue: 4, Pages: 593-607
ISSN:1432-2013
DOI:10.1007/s00424-015-1764-7
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s00424-015-1764-7
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Author Notes: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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Summary: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.
Item Description:Published online: 3 December 2015
Gesehen am 05.05.2020
Physical Description:Online Resource
ISSN:1432-2013
DOI:10.1007/s00424-015-1764-7

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