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

## TL;DR

Deleting the TRPC1 channel in mice with Fragile X syndrome reduces abnormal brain activity and improves memory and social behavior.

## Contribution

Conditional deletion of TRPC1 in FXS mice reveals its role in modulating mGluR5 signaling and memory extinction.

## Key findings

- TRPC1 deletion normalizes mGluR5-evoked currents in FXS neurons.
- Deleting Trpc1 inhibits mGluR5-induced long-term depression and improves memory extinction.
- TRPC1 mediates mGluR5 signaling through eEF2K- and ERK1/2-dependent pathways.

## 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.

•mGluR5 activates TRPC1 channel, triggering eEF2/ERK1/2 and ARC expression•mGluR5-induced currents are higher in FXS vs. WT and drop with Trpc1 gene deletion•Trpc1 gene deletion inhibits mGluR5-induced LTD•Trpc1 gene deletion corrects the exaggeratedly rapid memory extinction observed in FXS

mGluR5 activates TRPC1 channel, triggering eEF2/ERK1/2 and ARC expression

mGluR5-induced currents are higher in FXS vs. WT and drop with Trpc1 gene deletion

Trpc1 gene deletion inhibits mGluR5-induced LTD

Trpc1 gene deletion corrects the exaggeratedly rapid memory extinction observed in FXS

Genetics; Molecular biology; Neuroscience