Intrinsic activation of GABA(A) receptors suppresses epileptiform activity in the cerebral cortex of immature mice.

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Richter D, Luhmann HJ, Kilb W

Intrinsic activation of GABA(A) receptors suppresses epileptiform activity in the cerebral cortex of immature mice.

Epilepsia. 2010 Aug;51(8):1483-92. doi: 10.1111/j.1528-1167.2010.02591.x. Epub 2010 May 14.

PubMed ID

20491873 [ View in PubMed

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Abstract

PURPOSE: Activation of ionotropic gamma-aminobutyric acid type A (GABA(A) ) receptors induces in immature neocortical neurons a membrane depolarization that may contribute to the higher epilepsy susceptibility in newborns. To elucidate whether depolarizing GABAergic responses enhance or attenuate epileptiform activity in the immature neocortex, we investigated the effect of agonists, antagonists, and positive modulators of GABA(A) receptors on epileptiform activity. METHODS: We performed in vitro field potential recordings on isolated whole neocortex preparations and whole cell recordings of identified pyramidal neurons in 400-mum slices of immature (postnatal day 1-7) mice. Epileptiform activity was induced by low Mg(2)(+) solutions with or without 50-100 mum 4-aminopyridine. RESULTS: Bath application of GABA (3-100 mum, in the presence of tiagabine) attenuated epileptiform activity. The GABA transporter isoform 1 (GAT-1) inhibitor tiagabine (30 mum) and the GAT-2/3 specific inhibitor SNAP 5114 (40 mum) reduced the frequency of epileptiform activity. The benzodiazepines midazolam (0.2 mum) and zolpidem (0.5 mum) as well as the barbiturate phenobarbital (30 mum) slightly attenuated epileptiform activity. Continuous bath application of the GABAergic antagonist gabazine (SR-95531, 2-3 mum) or picrotoxin (15 mum) induced epileptiform discharges. DISCUSSION: These results demonstrate, that (1) the activation or positive modulation of GABA(A) receptors attenuates epileptiform activity, (2) GABA(A) antagonists mediate a disinhibition, and (3) GABA uptake contributes to the regulation of extracellular GABA in immature neocortex. We conclude from these findings that a constant inhibition via GABA(A) receptors is required to suppress epileptiform activity already in the immature neocortex.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Picrotoxin	Gamma-aminobutyric acid receptor subunit alpha-1	Protein	Humans	Yes	Antagonist	Details
Picrotoxin	Gamma-aminobutyric acid receptor subunit rho-1	Protein	Humans	Yes	Antagonist	Details