Abstracts

Based on histopathology, cortical dysplasias (CD) are classified into mild CD if the cortex shows architectural abnormalities only and severe CD if the cortex also presents cytomegalic neurons and balloon cells in addition to architectural changes. Both types induce intractable seizures in children. We showed that GABAergic cell numbers and GABA terminals were altered in severe CD but not in mild CD. GABA peak currents, densities and desensitization time constants were also differentially altered in mild and severe CD, suggesting that mechanisms of seizure induction might be different in those two types of pediatric CD (Andre et al., Epilepsia 46 Suppl. 8: 5, 2005). The present study characterized further postsynaptic GABA[sub]A[/sub] receptor function in non-CD, mild and severe CD human brain., Cortical samples resected for the treatment of pharmaco-resistant epilepsy were collected from non-CD (n = 10), mild (n = 6) and severe CD (n = 10) patients. Brain tissue slices were acutely dissociated and electrophysiological recordings were performed on isolated pyramidal neurons. Patch electrodes were filled with N-methyl-D-glucamine for whole-cell voltage clamp recordings. Different concentrations of GABA and GABA[sub]A[/sub] receptor modulators were applied to the cells., EC[sub]50[/sub] values were similar in non-CD and severe CD but higher in mild CD cells suggesting less sensitive GABA[sub]A[/sub] receptors. Zinc reversibly decreased GABA peak currents in all cells. However, severe CD cells had a smaller sensitivity to zinc compared to non-CD cells. Zolpidem, a benzodiazepine (BZ) of type I that binds specifically to [alpha]1 subunits, reversibly enhanced GABA peak currents in all cells. Zolpidem sensitivity was significantly smaller in severe CD cells compared to mild and non-CD cells., GABA sensitivity determined by EC[sub]50[/sub] values was similar in non-CD and severe CD cells. However, GABA[sub]A[/sub] receptors responded differently to modulators in severe CD vs non-CD. Sensitivity to zinc was smaller in severe CD, suggesting higher expression of [gamma]2 subunits. Zolpidem effect was also decreased in severe CD vs non-CD indicating a decreased expression of [alpha]1. As [alpha]1 and [gamma]2 subunits are part of the BZ binding site, alteration in their expression is likely to change the efficacy of BZ used to treat seizures in severe CD. In mild CD, effects of modulators binding to [alpha]1- and [gamma]2-containing receptors were not different from non-CD indicating those subunits are not altered. However, GABA sensitivity was lower in mild CD, which could implicate a loss of inhibition and lead to seizures. Together, these results indicate that GABA[sub]A[/sub] receptor subunit composition is differentially altered in mild and severe CD and suggest that different drugs targeting GABA function might be needed to treat the two types of CD., (Supported by NIH NS38992.)