Conditional deletion of TRPC1 channel modulates synaptic plasticity, long term depression, and memory extinction in Fragile X Syndrome mice.

Issa, Farah;Yerna, Xavier;Parpaite, Thibaud;Jabbour, Caren;Gailly, Philippe;et.al.
(2025) iScience — Vol. 28, n° 8, p. 113085 (2025)

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Abstract
Group I metabotropic glutamate receptors (mGluRs), particularly mGluR5, regulate synaptic plasticity via long-term depression (mGluR-LTD), a process implicated in declarative memory. We previously identified TRPC1, a highly expressed hippocampal ion channel, as a key mGluR5 effector. Using a Cre-tamoxifen system, we acutely deleted Trpc1 in a Fragile X syndrome (FXS) mouse model, characterized by mGluR5 hyperactivity, enhanced mGluR-LTD, and social deficits. In FXS neurons, mGluR5-evoked currents were elevated and normalized by Trpc1 deletion. This deletion also improved social behavior and reduced anxiety. Notably, it abolished mGluR-LTD and normalized memory extinction, as shown in behavioral assays. Mechanistically, mGluR5 activation induced ARC protein expression via eEF2K- and ERK1/2-dependent pathways, modulating Arc translation and transcription. These findings highlight TRPC1 as a crucial mediator of pathological plasticity in FXS and a potential therapeutic target.
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Issa, F., Yerna, X., Parpaite, T., Jabbour, C., Schakman, O., Tajeddine, N., Gualdani, R., & Gailly, P. (2025). Conditional deletion of TRPC1 channel modulates synaptic plasticity, long term depression, and memory extinction in Fragile X Syndrome mice. iScience, 28(8), 113085. https://hdl.handle.net/2078.5/247305 (Original work published 2025)