Abstracts

Rationale: In the immature brain, GABA_A receptor (GABA_AR) activation is excitatory while in the adult brain it is inhibitory. The effects of GABA depend on the intracellular Cl^- concentration. The intracellular Cl^- concentration is regulated by the expression of two ion pumps: NKCC1 (chloride importer) and KCC2 (chloride exporter). We hypothesize that differences in cortical vs. subcortical neuronal maturation of these Cl^- transporters are responsible for the different effects of GABA in cortical vs. subcortical structures, and consequently, the electroclinical dissociation of neonatal seizures. Methods: Extracellular multi-unit activity was recorded from the hippocampus, amygdala, thalamus and neocortex using mice brain slices. Epileptiform activity was induced with 0 MgCl₂. Results: Isoguvacine, a GABA_AR agonist, increased action potential frequency in the hippocampus (P3-8). In contrast, at P3-8 isoguvacine was inhibitory in the amygdala. Similarly, isoguvacine was inhibitory in the thalamus but excitatory in the neocortex during early development. During seizures recorded in vitro, phenobarbital application induced a significant decrease in the seizure power in the amygdala with only modest effects in the hippocampus. During thalamocortical seizures, phenobarbital decreased the power of seizures in the thalamus but was ineffective in the neocortex. However, when bumetanide, an NKKC1 antagonist, was co-applied with phenobarbital, seizure power was decreased in the neocortex, but there was no difference vs. phenobarbital alone in thalamus. Conclusions: Our data support differing ontogeny of Cl^- transport in sub-cortical vs. cortical brain structures as a mechanism of electroclinical dissociation in neonatal seizures.