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.
Highlights
The cellular and molecular mechanisms underlying cognitive brain functions and their deterioration by neurodegenerative and neuropsychiatric disorders are a central theme in contemporary neuroscience
Many proteins and molecules have been reported to be important for longterm potentiation (LTP) expression, but only a few have been identified as critical for LTP induction, such as calcium/calmodulin-dependent protein kinase II (CaMKII), cyclic adenosine monophosphate-dependent protein kinase (PKA), protein kinase C (PKC), and the extracellular signal-regulated kinase (Erk)/mitogen-activated protein kinase (MAPK) pathway [7]
In order to decipher whether the lack of LTP in Trpm4−/− was due to a specific defect in the induction or the expression phase, we investigated the phosphorylation state of Ca2+/calmodulin-dependent kinase II (CamKII), which is known to be the first step of the signaling cascade upon Ca2+ influx through NMDA
Summary
The cellular and molecular mechanisms underlying cognitive brain functions and their deterioration by neurodegenerative and neuropsychiatric disorders are a central theme in contemporary neuroscience. At the level of individual synaptic connections, this is reflected in either long-lasting increases in synaptic efficacy (long-term potentiation (LTP)), long-lasting decreases (LTD), or a reset of previously increased or decreased efficacy to a new level (depotentiation and dedepression, respectively). Of these different forms of synaptic plasticity, LTP was the first that was discovered in the hippocampal formation [2]. Once the increase in intracellular Ca2+ exceeds a critical threshold value, biochemical processes necessary for LTP induction and expression are activated by molecular crosstalk within the multiprotein complex of the post-synaptic density (PSD) [20]. In contrast to the increasing complexity of LTP mechanisms downstream of NMDAR activation, the upstream mechanisms of post-synaptic depolarization in response to pre-synaptic glutamate release are fairly established during the last decades, pointing to a dominant contribution of AMPA receptors modulated by dendritic voltage-gated Ca2+, Na+, K+, and Ih channels [3]
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