Impairments in synaptic inhibition and glucose hypometabolism contribute to epileptogenesis in Wistar Audiogenic Rats with cortical malformation

Abstract

Epilepsy associated with malformations of cortical development (MCD) is often characterized by impaired cortical inhibition and altered brain metabolism, both of which play a key role in epileptogenesis. Recently, we reported the Wistar Audiogenic Rat (WAR), an epileptic-prone strain with induced cortical microgyria, exhibited increased ictogenesis and enhanced local cortical network synchrony, making it a reliable model to study epileptogenesis during development. The present study aimed to evaluate synaptic inhibition and glucose metabolism in several brain regions of this two-hit model of epilepsy (WAR-MCD) during the development. Unilateral cortical microgyria was induced via freeze-lesion in male and female neonatal WARs. Spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) were recorded in cortical pyramidal neurons adjacent to, distant from the microgyria, and the contralateral hemisphere during the juvenile and adolescent periods. Additionally, in vivo brain glucose metabolism was assessed during the same periods using [¹⁸F]FDG Positron Emission Tomography (PET) imaging. We observed significant reductions in amplitude, frequency and altered kinetics of sIPSCs in pyramidal neurons of MCD rats during the juvenile period. Synaptic inhibition deficits in paramicrogyral and contralateral cortices were even more pronounced in the two-hit model during adolescence. Glucose hypometabolism was evident in several brain regions of WARs and was further intensified in the two-hit model. These findings suggest an age-dependent disruption of cortical inhibition and glucose metabolism associated with MCD, further exacerbated by pro-epileptic conditions, contributing to epileptogenesis.