Heteromeric channels formed by TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and working memory |
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| Authors: | Jenny Bröker‐Lai Ilka Mathar Raul Guzman Yvonne Schwarz Alan Lai Petra Weißgerber Herbert Schwegler Alexander Dietrich Martin Both Rolf Sprengel Andreas Draguhn Georg Köhr Bernd Fakler Veit Flockerzi Dieter Bruns Marc Freichel |
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| Institution: | 1. Institute of Pharmacology, Heidelberg University, Heidelberg, Germany;2. Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany;3. Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany;4. Institute of Anatomy, University of Magdeburg, Magdeburg, Germany;5. Walther‐Straub‐Institute for Pharmacology and Toxicology, Ludwig‐Maximilians‐University München, München, Germany;6. Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany;7. Max Planck Research Group of the Max Planck Institute for Medical Research at the Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany;8. Physiology of Neural Networks, Psychiatry/Psychopharmacology, Central Institute of Mental Health, J5, Heidelberg University, Mannheim, Germany;9. Institute of Physiology, University of Freiburg, Freiburg, Germany;10. BIOSS, Center for Biological Signaling Studies, University of Freiburg, Freiburg, Germany? |
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| Abstract: | Canonical transient receptor potential (TRPC) channels influence various neuronal functions. Using quantitative high‐resolution mass spectrometry, we demonstrate that TRPC1, TRPC4, and TRPC5 assemble into heteromultimers with each other, but not with other TRP family members in the mouse brain and hippocampus. In hippocampal neurons from Trpc1/Trpc4/Trpc5‐triple‐knockout (Trpc1/4/5?/?) mice, lacking any TRPC1‐, TRPC4‐, or TRPC5‐containing channels, action potential‐triggered excitatory postsynaptic currents (EPSCs) were significantly reduced, whereas frequency, amplitude, and kinetics of quantal miniature EPSC signaling remained unchanged. Likewise, evoked postsynaptic responses in hippocampal slice recordings and transient potentiation after tetanic stimulation were decreased. In vivo, Trpc1/4/5?/? mice displayed impaired cross‐frequency coupling in hippocampal networks and deficits in spatial working memory, while spatial reference memory was unaltered. Trpc1/4/5?/? animals also exhibited deficiencies in adapting to a new challenge in a relearning task. Our results indicate the contribution of heteromultimeric channels from TRPC1, TRPC4, and TRPC5 subunits to the regulation of mechanisms underlying spatial working memory and flexible relearning by facilitating proper synaptic transmission in hippocampal neurons. |
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| Keywords: | cross‐frequency coupling hippocampal synaptic transmission relearning spatial working memory TRPC1/C4/C5 heteromeric assembly |
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