Heteromeric channels formed by TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and working memory. (8th August 2017) - Bröker‐Lai, Jenny
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. Synopsis: Heteromers from TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and specific mnemonic behavior. TRPC1, TRPC4, and TRPC5 assemble into heteromultimers with each other, but not with other TRP family members in the mouse brain and hippocampus. TRPC1/4/5 deficiency reduced action potential evoked responses in vitro and in situ, but LTP and depotentiation remained unchanged. In Trpc1/4/5 triple knockout mice cross‐frequency phase‐amplitude coupling is impaired while basal neuronal network oscillations are unchanged. Trpc1/4/5 triple knock out mice display deficits in spatial working memory and when adapting to a new challenge in a re‐learning task, whereas the acquisition of spatial reference memory remains unaltered. Abstract : Spatial working memory and flexible relearning requires the formation and function of hetero‐multimeric complexes of specific TRP channels in the mouse brain.