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Anticonvulsant Action of GABA in the High Potassium–Low Magnesium Model of Ictogenesis in the Neonatal Rat Hippocampus In Vivo and In Vitro

¹Section of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, Lebanon, New Hampshire; ²Institut de NeuroBiologie de la Méditerraneé, Institut National de la Santé et de la Recherche Médicale U29, Marseille, France

Submitted 8 February 2005; accepted in final form 29 June 2005

Previous developmental studies in vitro suggested that the inhibitory neurotransmitter GABA exerts depolarizing and excitatory actions on the immature neurons and that depolarizing GABA is causally linked to ictal activity during the first weeks of postnatal life. However, remarkably little is known on the role of GABA in the generation of neonatal seizures in vivo. Here, using extracellular recordings from CA3 hippocampus, we studied the effects of GABA_A-acting drugs on electrographic seizures induced by local intrahippocampal injection of the epileptogenic agents (high K⁺/low Mg²⁺) in the nonanesthetized rats in vivo and in the hippocampal slices in vitro during the second postnatal week (postnatal days P8-12). We found that in vivo, the induction of ictal-like events was facilitated by co-infusion of high-K⁺/low Mg²⁺ together with the GABA_A antagonist bicuculline or gabazine. Moreover, the infusion of bicuculline alone caused ictal-like activity in 30% of cases. Co-infusion of the GABA_A receptor agonist isoguvacine or the GABA_A-positive allosteric modulator diazepam completely prevented high-K⁺/low Mg²⁺-induced seizures. In in vitro studies using hippocampal slices, we also found that high-K⁺/low Mg²⁺ produced ictal activity that was exacerbated by bicuculline and gabazine and reduced by isoguvacine. Thus in the model of high-K⁺/low Mg²⁺-induced seizures both in in vivo and in vitro conditions, GABA, acting via GABA_A receptors, has an anticonvulsant effect during the critical developmental period of enhanced excitability.

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