PAK1 Is Involved in Epileptogenesis by Regulating the Synaptic Plasticity of Hippocampal Neurons Through LIMK

PAK1, a key regulator of cytoskeletal remodeling, is associated with synaptic plasticity, but its role in epilepsy remains unclear. This study investigated whether PAK1 contributes to epileptogenesis by modulating hippocampal synaptic plasticity via the LIMK signalling pathway. A chronic epilepsy model was induced in mice via the use of pentylenetetrazol (PTZ). LV-PAK1-shRNA was stereotactically injected into the hippocampus to downregulate PAK1. Seizure susceptibility was evaluated through seizure scores and latency to kindling. Western blotting was used to assess the expression of PAK1, LIMK1/2, and phosphorylated LIMK1/2 (p-LIMK1/2). Golgi-Cox staining and transmission electron microscopy were used to analyze dendritic spine density and the number of synaptic vesicles in the CA1 region. Epileptic mice presented increased hippocampal expression of PAK1, LIMK1/2, and p-LIMK1/2. PAK1 knockdown reduced LIMK1/2 and p-LIMK1/2 levels, decreased seizure severity, and delayed epileptogenesis. It also significantly reduced the dendritic spine density and number of synaptic vesicles in CA1 neurons. PAK1 may contribute to epileptogenesis by regulating dendritic spine formation and synaptic vesicle availability via the LIMK pathway, highlighting its potential as a therapeutic target for epilepsy.