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Article 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 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 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 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329558 | PMC |
| http://dx.doi.org/10.1016/j.isci.2025.113085 | DOI Listing |
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