The postsynaptic scaffold protein ABLIM1 regulates seizure susceptibility by maintaining GluA2 membrane localization...

Temporal lobe epilepsy (TLE), the most common form of drug-resistant epilepsy (DRE) in adults, is a frequent chronic neurological disorder. Nevertheless, the precise pathophysiological mechanisms underlying TLE remain largely undefined. Our findings demonstrate that Actin-binding LIM protein 1 (ABLIM1) is broadly expressed in the adult mouse brain, with high expression in the hippocampus. The protein is primarily localized to neurons, enriched in the postsynaptic density (PSD), colocalizes with the scaffold protein PSD95, and directly binds to F-actin. Co-IP experiments confirmed that ABLIM1 interacts with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits GluA1 and GluA2. Following hippocampal stereotaxic injection of adeno-associated virus (AAV) to specifically knock down ABLIM1 expression, we observed reduced F-actin polymerization, decreased dendritic spine density, and thinning of the PSD in the mouse hippocampus. In the chronic epilepsy models induced by kainic acid (KA), ABLIM1 knockdown significantly exacerbated seizure severity and increased seizure susceptibility. Further mechanistic studies revealed that ABLIM1 knockdown specifically reduces membrane expression of GluA2 without altering its total protein levels. Collectively, ABLIM1 may regulate epileptogenesis and disease progression by maintaining postsynaptic structural integrity and GluA2 membrane homeostasis. Thus, the ABLIM1-GluA2 signaling axis represents a potential therapeutic target for DRE.