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 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.

Parameter tuning differentiates granule cell subtypes enriching the repertoire of retransmission properties at the cerebellum input stage

“…Acceleration was correlated with the TRPM4 current and modeling predicted that the TRPM4 channels, coupled to Calmodulin through intracellular Ca 2+ changes, could effectively generate firing acceleration about 1.5 seconds after the beginning of discharge, i.e. when acceleration was observed experimentally (Shin et al, 2008;Shin et al, 2009;Kim et al, 2013;Menigoz et al, 2016). This delay reflected the slow cooperative gating of TRPM4 channels, that opened only after the Ca 2+ -Calmodulin complex reached a threshold.…”

“…The depolarization-induced slow current (DISC) is a depolarizing current gated by the raise of intracellular Ca 2+ that follows action potential bursts and NMDA channel activation, and can typically generate a secondary burst after 1.5-2 secs like that observed in accelerating GrCs (Shin et al, 2008;Shin et al, 2009;Menigoz et al, 2016). DISC is typically generated by TRPM4 (Kim et al, 2013), a Ca 2+ -activated non-selective cation channel which provides a strong depolarizing drive upon Ca 2+ entry (Petersen, 2002).…”

“…In excitable cells, it is regarded as the most suitable signaling mechanism to boost the depolarizing drive following an increase in electrical activity, which reflects into the activation of voltage-gated Ca 2+ channels (Petersen, 2002). Emerging evidence showed that TRPM4 is actually recruited by an increase in cytosolic Ca 2+ concentration to generate a DISC current and finely tune neuronal excitability in several brain areas (Lei et al, 2014;Menigoz et al, 2016;Riquelme et al, 2018). For instance, TRPM4 mediates the depolarizing afterpotential and phasic bursting observed in supraoptic and periventricular nuclei of the hypothalamus after a train of action potentials (Teruyama et al, 2011) and contributes to increase the firing rate in PCs (Kim et al, 2013).…”

Subcellular Localization and Activity of TRPM4 in Medial Prefrontal Cortex Layer 2/3

“…TRPM4 expression in substantia nigra pars compacta may play an important role in the plateau potential and burst firing of dopaminergic neurons ( Mrejeru et al, 2011 ). Additionally, TRPM4 participates in the dendritic depolarization necessary to induce certain forms of LTP in the hippocampal CA1 area ( Menigoz et al, 2016 ). Recently, Lei et al (2014) demonstrated that TRPM4 is expressed in pyramidal neurons of layer 5 in mouse mPFC.…”

Glutamate receptor GluA1 subunit is implicated in capsaicin induced modulation of amygdala LTP but not LTD

“…Members of the transient receptor potential (TRP) channel family, a family of nonselective cation channels, have been shown to modify synaptic plasticity in various brain regions including the hippocampus (Gibson et al 2008;Li et al 2008;Chávez et al 2010;Menigoz et al 2016), entorhinal cortex (Banke 2016), nucleus accumbens (Grueter et al 2010), and superior colliculus (Maione et al 2009). In the LA, we have previously demonstrated that LTP is attenuated by capsaicin via activation of TRPV1 (Zschenderlein et al 2011) whereas LTD is enhanced by capsaicin via activation of TRPM1 (Gebhardt et al 2016).…”