GABAA Receptor-Mediated Epileptogenicity in Focal Cortical Dysplasia (FCD) Depends on Age at Epilepsy Onset

Abstract

Enhanced spontaneous GABA A receptor activity is associated with focal cortical dysplasia (FCD), a developmental malformation of the cerebral cortex. Clinical manifestations in FCD vary with age at epilepsy onset with a more favorable prognosis in patients with late-onset (LO) compared to that in cases with early-onset (EO). This study was designed to test the hypothesis in FCD that spontaneous GABA A receptor-mediated epileptogenicity depends on the age at epilepsy onset and varies between patients with early and late-onset age in FCD. To this end, brain specimens were obtained from the maximal spiking region (MAX) and minimal spiking region (MIN) of the epileptic foci of EO (n = 14, mean age = 10.6 ± 2.9 years) and LO (n = 10, mean age = 27 ± 5.6 years) patients undergoing electrocorticography (ECoG) guided surgery. The whole-cell patchclamp technique was used to record spontaneous GABAergic currents from normallooking pyramidal neurons in slice preparations of resected brain samples. We detected higher frequency and amplitude of GABAergic events in MAX samples compared to MIN samples of LO patients, while they were comparable in MIN and MAX samples of EO patients. Further GABAergic activity in the MIN and MAX samples of EO patients was higher than the MIN samples of LO patients. This suggests that in LO patients, GABA A receptor-mediated epileptogenicity is confined only to the high spiking areas, but in EO patients, it affects low spiking regions as well.

Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients

“…P2X7 receptor ligands may be considered as a therapeutic target for DRE [ 82 ]. High SLC12A2 expression results in elevated Cl- concentration inside the cell, leading to net Cl − outflow and subsequent depolarization when GABA activates GABA A Rs [ 83 , 84 ]. Increased expression of SLC12A2 has been reported in surgically resected tissue specimens from FCD patients [ 85 ].…”