Partial restoration of physiological UP-state activity by GABA pathway modulation in an acute brain slice model of epilepsy

Abstract

In addition to reducing seizures, anti-epileptic treatments should preserve physiological network activity. Here, we used a thalamocortical slice preparation displaying physiological slow oscillations to investigate the effects of anticonvulsant drugs on physiological activity and epileptiform activity in two pharmacological epilepsy models. Thus, we compared the effects of GABA pharmacology on spontaneous physiological and pathological events in slices of the mouse barrel cortex. We show that both reducing inhibition using GABA_AR blockers and enhancing excitation by lowering Mg²⁺ concentration allow for the transition from physiological slow oscillations to epileptiform activity. Our results indicate that GABA_BR antagonists have pro-convulsive properties by increasing event duration in the low inhibition model and event frequency in the high excitation model. Moreover, we show that GABA_BR agonists and GABA uptake blockers, known for their anticonvulsant properties, act primarily on epileptiform burst frequency and allow for a partial restoration of physiological events. As a proof of principle, these results indicate that a slice model with spontaneous network events may be a useful pipeline to investigate the effects of anti-epileptic drugs on both epileptiform and physiological network activity.