Bestrophin1-mediated GABA release activates large chloride currents to generate epileptiform events in the entorhinal cortex
Scalmani, P.; Uva, L. M.; Regondi, M. C.; Miele, C.; Grazioso, V.; de Curtis, M.
Show abstract
The mechanisms that lead to the onset of a focal seizure are still not understood. We used the well-established 4-aminopyridine (4AP) ictogenesis model to analyze epileptiform discharges in the entorhinal cortex of rodents maintained in vitro. Simultaneous field potential and patch-clamp recordings demonstrated that 100 {micro}M 4AP elicited periodic and large chloride currents in both principal neurons and GABAergic interneurons that steadily matched with population spikes. These population spike-associated chloride currents (PSACCs) survived glutamate and glycine receptor blockade and were abolished by GABAA antagonists and by blocking synaptic neurotransmitters release. Antagonist of astrocyte bestrophin-1 channels inhibited PSACCs and prevented the occurrence of seizure-like events in both entorhinal cortex mouse slices and in the isolated guinea pig brain. We propose that bestrophin-1-induced GABA release likely triggered by astrocytes promotes in all neurons subtypes a large chloride current that is responsible for interictal spikes and establishes the conditions for the generation of seizure-like events.
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