Compromising KCC2 transporter activity enhances the development of continuous seizure activity.

摘要: Impaired neuronal inhibition has long been associated with the increased probability of seizure occurrence and heightened severity. Fast synaptic in brain is primarily mediated by type A γ-aminobutyric acid receptors (GABAARs), ligand-gated ion channels that can mediate Cl(-) influx resulting membrane hyperpolarization restriction firing. In most adult neurons, K(+)/Cl(-) co-transporter-2 (KCC2) establishes hyperpolarizing GABAergic maintaining low [Cl(-)]i. this study, we sought to understand how decreased KCC2 transport function affects event We impaired 0-Mg(2+) ACSF 4-aminopyridine in vitro models epileptiform activity acute mouse slices. Experiments selective inhibitor VU0463271 demonstrated reduced duration SLEs, non-terminating discharges clonic-like activity. also investigated slices obtained from KCC2-Ser940Ala (S940A) point-mutant mouse, which a mutation at known functional phosphorylation site causing behavioral cellular deficits under hyperexcitable conditions. recorded entorhinal cortex S940A both 4-aminopyridine, loss S940 residue susceptibility continuous discharges, an form status epilepticus. Our experiments revealed critical factor mechanisms termination. results highlight need for therapeutic strategies potentiate order decrease severity prevent development