A glibenclamide-sensitive TRPM4-mediated component of CA1 excitatory postsynaptic potentials appears in experimental autoimmune encephalomyelitis

Abstract

The transient receptor potential melastatin 4 (TRPM4) channel contributes to disease severity in the murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and to neuronal cell death in models of excitotoxicity and traumatic brain injury. As TRPM4 is activated by intracellular calcium and conducts monovalent cations, we hypothesized that TRPM4 may contribute to and boost excitatory synaptic transmission in CA1 pyramidal neurons of the hippocampus. Using single-spine calcium imaging and electrophysiology, we found no effect of the TRPM4 antagonists 9-phenanthrol and glibenclamide on synaptic transmission in hippocampal slices from healthy mice. In contrast, glibenclamide but not 9-phenanthrol reduced excitatory synaptic potentials in slices from EAE mice, an effect that was absent in slices from EAE mice lacking TRPM4. We conclude that TRPM4 plays little role in basal hippocampal synaptic transmission, but a glibenclamide-sensitive TRPM4-mediated contribution to excitatory postsynaptic responses is upregulated at the acute phase of EAE.

Transient receptor potential melastatin 4 (TRPM4) regulates hilar mossy cell loss in temporal lobe epilepsy

“…To examine whether Trpm4 is expressed in hilar MC cells, we used RNA scope in situ hybridization for its high sensitivity to detect even low level of expression. Unfortunately, immune-histochemical detection of TRPM4 protein is often controversial in the literature[21]. Using RNA scope in situ hybridization within the hippocampal formation, we found abundant Trpm4 mRNA expression primarily in the hilar region (Figure 1 A-C).…”

“…Expression pattern of TRPM4 in the brain is controversial because of the lack of selective antibodies. Several studies suggested the role of TRPM4 in neuronal function on different brain regions including the hippocampus[21][31][32] the prefrontal cortex[33] and the pre-Bötzinger[34] complex however, most of these publications used pharmacological tools with questionable selectivity[25] to investigate TRPM4 function. Recently, two studies proved the expression of Trpm4 in brainstem pacemaker neurons using the ultrasensitive RNAscope in situ hybridization technique[35][36].…”

TRPM4 regulates hilar mossy cell loss in temporal lobe epilepsy

“…To examine whether Trpm4 is expressed in hilar MCs, we used RNAscope in situ hybridization for its high sensitivity to detect even low level of expression. Unfortunately, immune-histochemical detection of TRPM4 protein is often controversial in the literature [ 19 ]. Using RNAscope in situ hybridization within the hippocampal formation, we found abundant Trpm4 mRNA expression primarily in the hilar region (Fig.…”

“…Expression pattern of TRPM4 in the brain is controversial because of the lack of selective antibodies. Several studies suggested the role of TRPM4 in neuronal function on different brain regions including the hippocampus [ 19 , 30 , 31 ], the prefrontal cortex [ 32 ], and the pre-Bötzinger [ 33 ] complex; however, most of these publications used pharmacological tools with questionable selectivity [ 24 ] to investigate TRPM4 function. Recently, two studies proved the expression of Trpm4 in brainstem pacemaker neurons using the ultrasensitive RNAscope in situ hybridization technique [ 34 , 35 ].…”

Exploring the role of TRPM4 in calcium‐dependent triggered activity and cardiac arrhythmias

“…Mechanisms of altered excitability are often shared between cardiomyocytes and CNS neurons (Halvorsen et al., 2021). In CNS neurons, TRPM4 is involved in specific types of hippocampal synaptic plasticity and learning, but also glutamate cytotoxicity (Fearey et al., 2022; Gerzanich et al., 2009; Schattling et al., 2012; Simard & Gerzanich, 2018). In vitro experiments in hippocampal slices have reported a lack of long‐term potentiation (LTP) in Trpm4 −/− mice (Bovet‐Carmona et al., 2018, 2019; Menigoz et al., 2016).…”