Disentangling the role of TRPM4 in hippocampus-dependent plasticity and learning: an electrophysiological, behavioral and FMRI approach

Abstract

Hippocampal long-term potentiation (LTP) has been extensively studied as a cellular model of learning and memory. Recently, we described a central function of the Transient Receptor Potential M4 (TRPM4) channel in hippocampal LTP in mice in vitro. Here, we used Trpm4 knock-out (Trpm4) rats to scrutinize TRPM4's role in the intact brain in vivo. After having confirmed the previous in vitro findings in mice, we studied hippocampal synaptic plasticity by chronic recordings in freely moving rats, hippocampus-dependent learning by a behavioral battery and hippocampal-cortical connectivity by fMRI. The electrophysiological investigation supports an involvement of TRPM4 in LTP depending on the induction protocol. Moreover, an exhaustive analysis of the LTP kinetics point to mechanistic changes in LTP by trpm4 deletion. General behavior as measured by open field test, light-dark box and elevated plus maze was inconspicuous in Trpm4 rats. However, they showed a distinct deficit in spatial working and reference memory associated to the Barnes maze and T-maze test, respectively. In contrast, performance of the Trpm4 in the Morris water maze was unaltered. Finally, fMRI investigation of the effects of a strong LTP induction manifested BOLD responses in the ipsilateral and contralateral hippocampus and the prefrontal cortex of both groups. Yet, the initial BOLD response in the stimulated hippocampal area of Trpm4 was significantly enhanced compared to WT rats. Our findings at the cellular, behavioral and system level point to a relevant role for TRPM4 in specific types of hippocampal synaptic plasticity and learning but not in hippocampal-prefrontal interaction.

Electrical Stimulation of the Lateral Entorhinal Cortex Causes a Frequency-Specific BOLD Response Pattern in the Rat Brain

“…It appears that, in contrast to LEC projections, projections from the hippocampus proper/subiculum neurons, which are directly activated by perforant pathway fibers, are less efficient at triggering BOLD responses in the frontal cortex. This also supports recent findings that high-frequency pulse stimulation of Schaffer collaterals causes the formation of negative BOLD responses only in the mPFC (Bovet-Carmona et al, 2018) and that CA3 stimulation alleviates otherwise induced positive BOLD responses in the prefrontal cortex (Scherf and Angenstein, 2017). In particular, it appears that afferents from the LEC and CA1/subiculum elicit different BOLD responses in regions of the frontal cortex.…”

“…However, 10 and 20 Hz stimulation also elicited strong fMRI responses in the entorhinal cortex, whereas no significant fMRI responses in the entorhinal cortex were observed during all other stimulation frequencies. Similarly, direct electrical stimulation of Schaffer collaterals with high-frequency (200 Hz) pulse bursts caused significant positive fMRI responses in the ipsi- and contralateral hippocampus but, if at all, only negative BOLD responses in the mPFC (Bovet-Carmona et al, 2018); again, this stimulation did not trigger significant BOLD responses in the entorhinal cortex. Based on these results, we hypothesize that high-frequency (i.e., in the high gamma frequency range) pulse stimulation of the perforant pathway stimulation elicits significant positive BOLD responses in the prefrontal cortex mainly via entorhinal cortex projections.…”

TRPM3 in Brain (Patho)Physiology

“…Furthermore, TRPM7 is widely expressed in the brain, and was shown to be involved in cell growth (Turlova et al, 2016) and cell death after ischemic and hypoxic brain injuries (Aarts et al, 2003;Sun et al, 2009;Chen et al, 2015;Sun, 2017). TRPM4 was also reported to be involved in cognitive functions, as well as in (patho)physiological processes, such as hippocampal plasticity (Menigoz et al, 2016;Bovet-Carmona et al, 2018) or development of trauma induced brain edema (Gerzanich et al, 2019;Woo et al, 2020).…”

The TRPV Channel OSM-9 is Required Non-Cell Autonomously for Sleep-Dependent Olfactory Memory

“…In addition to the hippocampus, expression of TRPCs has been uncovered in the temporal lobe, suggesting a role in neural plasticity, learning, and memory. TRPM4 has also been found to be expressed in the mammalian hippocampus and is important for plasticity and spatial working and reference memory (Bovet-Carmona et al, 2018). Several recent studies have implicated mammalian TRPV1 in memory formation, including fear memory consolidation behavior in mice (Genro et al, 2012;Marsch et al, 2007;Li et al, 2008).…”