Activation of G protein-coupled estrogen receptor alleviates the abnormal changes of synaptic plasticity in the anterior insula of temporal lobe epilepsy rats through RhoA/Rock2 pathway.

Temporal lobe epilepsy (TLE) is the most common type of refractory epilepsy, characterized by highly synchronized abnormal neuronal discharge. The insula cortex (IC) serves as a key "node" in the TLE transmission network, and the anterior insula (AI) is a critical gatekeeper to executive control; however, the pathological changes of the IC/AI have been overlooked. GPER1 is a G protein coupled estrogen receptor anchored by PSD95 to the plasma membrane of dendritic spine (DS), participating in the regulation of DS plasticity. We found that Gper1 deletion rats exhibited increased susceptibility to epilepsy, but it remains unclear whether and how GPER1 regulates alterations in DS plasticity in the IC after TLE induction. Here, we observed that the interaction between GPER1 and PSD95 diminished at TLE induction 7 d, the dendrite complexity and DS density were altered in the AI. While, activating of GPER1 ameliorated the neuronal damage and loss in the AI of TLE rats, decreased dendrite complexity and increased DS density，enhanced the interaction between GPER1 and PSD95, then mitigated the inhibition of Rock2 and its downstream targets, cofilin and the imbalance of F/G-actin, which was induced by the over-activation of CAMKII and RhoA. Thus, improved the emotion and cognitive dysfunction of TLE rats. Our results offer compelling evidence for elucidating the mechanism of abnormal changes in insular synaptic plasticity following TLE and the selection of therapeutic targets.