Bestrophin1-mediated GABA release activates large chloride currents to generate epileptiform events in the entorhinal cortex

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 µM 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. Competing Interest Statement The authors have declared no competing interest. Footnotes Abbreviations Entorhinal cortex = EC; Population spike-associated chloride current (PSACC); Inhibitory postsynaptic current = IPSC; Seizure-like event = SLE; Local field potential = lfp; Pyramidal neuron = PN; Interneuron = IN; Green fluorescent protein = GFP; Y-aminobutyric acid = GABA; Kinurenic acid = KYN; 4-aminopyridine = 4AP; Gabazine = GBZ; Picrotoxin = PTX; Tetrodotoxin = TTX; Strychnine = STR; Cobalt chloride = CoCl2; Cadmium chloride = CdCl2; Excitatory aminoacid transporter = EAAT; 1,2,5,6-tetrahydro-1,2-diphenylmethylene-aminooxyethyl-3-pyridinecarboxylic acid = NO-711; 5-nitro-2-3-phenylpropylamino-benzoic acid = NPPB; DL-threo-beta-benzyloxyaspartate = TBOA; GABA transporter = GAT; Paraformaldehyde = PFA; Glial fibrillary acid protein = GFAP; 4,6-diamidino-2-phenylindole = DAPI.