Dual role of Spreading Depolarization in the epileptic focus

Abstract

Spreading Depolarizations (SDs) are often associated with epileptic discharges. While SDs are traditionally thought contributing to the postictal depression and termination of epileptic discharges, seizures may also occur during SDs or may even follow SDs suggesting that interactions between SD and seizures are more complex. Here, we examined the interactions between SD and epileptic activity by spatially separating the epileptic focus and the site of SD initiation. Epileptic focus was induced by local intracortical injection of the potassium channel blocker 4-AP combined with the GABA(A) receptor antagonist gabazine, whereas extrinsic SDs were evoked by distal high potassium application. We found that extrinsic SDs promoted seizure-like events (SLEs) when the SD wave approached the epileptic focus, followed by suppression of epileptic activity when SD spread through the focus. The timing of SLE relatively SD varied at different recordings sites, with SLEs occurring before, during or after SD arrival depending on electrode position along the trajectory of SD propagation between the SD initiation site and the epileptic focus. During intracortical recordings, the proconvulsive effects of SD were associated with a wave of pre-SD neuronal excitation reaching the epileptic focus. The epileptic focus per se also demonstrated a resistance to the SD invasion. Thus, the interactions between SD and epileptic focus are not limited to postictal depression, and SDs may also promote epileptic activity in the hyperexcitable cortex. Key pointsO_LIEffects of SD on epileptic focus are dual: both pro- and anticonvulsive C_LIO_LISDs promote epileptic discharges upon approaching the epileptic focus C_LIO_LIThe timing of epileptic discharges relatively SD varies along the SD trajectory C_LIO_LIProconvulsive effects of SD align with the pre-SD excitation C_LIO_LIEpileptic focus resists the SD propagation C_LI