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1 Medicine, Dartmouth Medical School, Lebanon, NH, USA
* To whom correspondence should be addressed. E-mail: Gregory.L.Holmes{at}Dartmouth.edu.
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 non-anaesthetized 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 about 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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