6533b82efe1ef96bd129450d

RESEARCH PRODUCT

Intrinsic activation of GABAA receptors suppresses epileptiform activity in the cerebral cortex of immature mice

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SUMMARY Purpose: Activation of ionotropic c-aminobutyric acid type A (GABAA) 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 GABAA 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-lm slices of immature (postnatal day 1–7) mice. Epileptiform activity was induced by low Mg 2+ solutions with or without 50–100 lM 4-aminopyridine. Results: Bath application of GABA (3–100 lM, in the presence of tiagabine) attenuated epileptiform activity. The GABA transporter isoform 1 (GAT-1) inhibitor tiagabine (30 lM) and the GAT-2/3 specific inhibitor SNAP 5114 (40 lM) reduced the frequency of epileptiform activity. The benzodiazepines midazolam (0.2 lM) and zolpidem (0.5 lM) as well as the barbiturate phenobarbital (30 lM) slightly attenuated epileptiform activity. Continuous bath application of the GABAergic antagonist gabazine (SR-95531, 2–3 lM) or picrotoxin (15 lM) induced epileptiform discharges. Discussion: These results demonstrate, that (1) the activation or positive modulation of GABAA receptors attenuates epileptiform activity, (2) GABAA 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 GABAA receptors is required to suppress epileptiform activity already in the immature neocortex.