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.
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Acknowledgements
This work was supported by the Fonds voor Wetenschappelijk Onderzoek (FWO) Flanderen, project G. 0A14.14N and the KU Leuven onderzoeksfonds (TRP Research Platform Leuven, TRPLe). Special thanks to Adam Raes and Tariq Ahmed for their methodical support and critical input, and to Nele De Ruyck for the help with behavior.
Funding
This work was supported by the Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen, project G. 0A14.14N and the KU Leuven onderzoeksfonds (TRP Research Platform Leuven, TRPLe).
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the European Community Council Directive (2010/63/EU) and following the regulations of and approved by the local ethics committee under the number P079/2013 and P143/2012, KU Leuven. This article does not contain any studies with human participants performed by any of the authors.
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Bovet-Carmona, M., Menigoz, A., Pinto, S. et al. Disentangling the role of TRPM4 in hippocampus-dependent plasticity and learning: an electrophysiological, behavioral and FMRI approach. Brain Struct Funct 223, 3557–3576 (2018). https://doi.org/10.1007/s00429-018-1706-1
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DOI: https://doi.org/10.1007/s00429-018-1706-1