GABAB-Dependent Negative Feedback Contributes to Earlier Epileptiform Discharge Termination Within Malformed Cortex

Abstract

Malformations of cortical development frequently underlie drug-resistant epilepsy, yet little is known about how malformed cortical networks terminate epileptiform activity. In acute cortical slices from juvenile male Wistar rats with a focal freeze lesion, we compared the microgyrus and paramicrogyral zone during low-Mg2+/gabazine-induced epileptiform activity. Discharges terminated earlier in the microgyrus than in the paramicrogyral zone (median, 268 vs. 496 ms), without detectable regional differences in peak discharge-associated inward current or the weighted decay time constant of extracellular K+ transients. In separate voltage-clamp recordings, the transition to a slow post-discharge outward current occurred earlier in microgyral neurons, and the current peaked sooner and showed a smaller normalized late component. GABAB receptor blockade with CGP-55845 prolonged discharges and preferentially disrupted the faster post-peak current decay in the microgyrus. Intracellular QX-314, used to probe a postsynaptic component, eliminated detectable regional differences in outward-current kinetics. Gabbr1 and Gabbr2 mRNA abundance did not differ detectably between the microgyrus and contralateral cortex. Overall, the findings support a postsynaptic GABAB-dependent contribution to earlier epileptiform discharge termination within the microgyrus. More broadly, malformation-associated reorganization includes local negative-feedback processes that constrain pathological network persistence alongside mechanisms that promote hyperexcitability.