Synaptic vesicle protein 2A regulates mossy fiber sprouting in a drug-resistant epilepsy rat model via laminin α5/integrin β1.

Abstract

Drug-resistant epilepsy (DRE) is frequently characterized by pathological mossy fiber sprouting (MFS), which is a defining indicator of aberrant synaptic remodeling within the hippocampus. Despite extensive investigations of the molecular underpinnings of MFS, they remain only partially elucidated. Synaptic vesicle protein 2 A (SV2A) is a key modulator of neurotransmitter exocytosis that has been associated with epileptogenesis. However, its involvement in structural neural plasticity throughout epileptogenic progression remains unclear. In this study, a pilocarpine-induced rat model of DRE was utilized to evaluate the influence of SV2A on MFS. Immunofluorescence, western blot analysis, and the lentivirus-mediated modulation of SV2A expression revealed that SV2A suppression intensified both MFS and seizure severity. Mechanistically, the results of co-immunoprecipitation combined with mass spectrometry suggested that a deficiency of SV2A could facilitate aberrant axonal sprouting via disruption of the laminin α5 (LAMA5)/integrin β1 (ITGB1) signaling cascade. Subsequent validation confirmed that decreased LAMA5 expression and attenuated ITGB1 activation in SV2A-deficient rats were contributory factors to pathological axonal sprouting. These findings implicate SV2A as a critical determinant of structural plasticity in epileptogenesis and highlight the LAMA5/ITGB1 axis as a promising therapeutic avenue for DRE.