This study investigates the impact of GPER1 knockout (GPER1-KO) on recognition memory and hippocampal synaptic plasticity in a rat model of epilepsy. Male Sprague-Dawley (SD) rats and GPER1-KO rats, aged 2 months, were divided into control and epilepsy groups (1, 3, 7, and 14 days post-status epilepticus, SE). Epilepsy was induced using lithium chloride-pilocarpine, and recognition memory was assessed via the Intellicage system, evaluating nose-poke learning, corner preference, and reversal learning. Synaptic plasticity was examined through EEG monitoring, Nissl, Timm, and Golgi staining, patch-clamp recordings, and electron microscopy to analyze neuronal morphology, mossy fiber sprouting (MFS), dendritic complexity, and long-term potentiation (LTP). Western blot analysis assessed CaMKⅡ, ROCK2, p-Cofilin, and F/G-actin ratios to explore underlying mechanisms. Results showed no significant differences in baseline behavior between wild-type (WT) and GPER1-KO groups. However, GPER1-KO-SE rats exhibited significantly reduced corner visits and nose-pokes compared to WT-SE rats, indicating worsened recognition memory impairment. EEG revealed increased δ and θ wave power in GPER1-KO-SE rats, suggesting exacerbated epileptiform activity. Nissl staining showed greater neuronal loss and morphological damage in GPER1-KO-SE rats, particularly at 7 days post-SE. Timm staining indicated increased MFS, while Golgi staining revealed reduced dendritic complexity and spine density in GPER1-KO-SE rats. Patch-clamp recordings demonstrated impaired LTP in the Schaffer collateral pathway in GPER1-KO-SE rats. Electron microscopy confirmed more severe ultrastructural damage in GPER1-KO-SE rats, including synaptic deterioration. Mechanistically, GPER1-KO-SE rats showed decreased CaMKⅡ and p-Cofilin expression, increased ROCK2 expression, and reduced F/G-actin ratios, suggesting enhanced Rho-ROCK2 pathway activation, leading to increased actin depolymerization and immature dendritic spines. In conclusion, GPER1-KO exacerbates recognition memory deficits and hippocampal synaptic plasticity impairments in epileptic rats, likely by activating the Rho-ROCK2 pathway, increasing MFS, reducing dendritic complexity, and impairing synaptic maturation. These findings highlight GPER1’s role in modulating epilepsy-related neurological impairments.

GPER1-KO, Epilepsy, Synaptic Plasticity, F-actin, G-actin