The role of TRPM4 in Hippocampus-dependent plasticity and learning: an electrophysiological, behavioral and fMRI approach

Hippocampal long-term potentiation (LTP) has been extensively studied as a cellular model of learning and memory. Induction of LTP in the Schaffer collateral commissural pathway of the hippocampal CA1-region typically involves postsynaptic calcium entry and subsequent activation of protein kinases that lead to a long-term increase in synaptic strength. A novel player in synaptic plasticity is the Transient Receptor Potential M4 (TRPM4) channel, a calcium-activated but calcium-impermeable non-selective cation channel. Here, we employed Trpm4 knockout (Trpm4-/-) rats to scrutinize TRPM4's role in the intact brain in vivo. We studied hippocampal synaptic plasticity by chronic recordings in the CA1 area of freely-moving rats, hippocampus-dependent learning by a behavioral battery and hippocampal-cortical connectivity by fMRI. The electrophysiological experiments support a differential involvement of TRPM4 in LTP depending of the strength of the induction protocol, suggesting mechanistic changes in LTP by Trpm4 deletion. This was corroborated by an exhaustive analysis of LTP kinetics by discrete-time transfer function models. The general behavior as measured by the open field test, light-dark box and elevated plus maze was inconspicuous in Trpm4-/- rats. When spatial learning was investigated by the Barnes maze, Trpm4-/- rats showed a distinct deficit in spatial reference and working memory, which was corroborated by the T-maze test. However, the performance of Trpm4-/- rats in the Morris water maze was unaltered. Finally, LTP induction in the CA1 area was simultaneously monitored by electrophysiology at the area of stimulation and BOLD fMRI measurements across the whole brain. Stimulus-related BOLD responses were found in the right and left dorsal hippocampus and parts of the prefrontal cortex. The general activation pattern, reflected by BOLD signal changes, was similar in the two genotypes. Yet, the initial BOLD response in the right hippocampal area after the first stimulation train was significantly enhanced in Trpm4-/- compared to control rats. Our findings at the cellular, behavioral and system level point to a relevant role for TRPM4 in specific types of synaptic plasticity and learning but not in hippocampal-extrahippocampal network activation.status: publishe