Anticonvulsant action of GABA in the high potassium-low magnesium model of ictogenesis in the neonatal rat hippocampus in vivo and in vitro.
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 Mg(2+)) 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 Mg(2+) together with the GABA(A) antagonist bicuculline or gabazine. Moreover, the infusion of bicuculline alone caused ictal-like activity in approximately 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 Mg(2+)-induced seizures. In in vitro studies using hippocampal slices, we also found that high-K(+)/low Mg(2+) produced ictal activity that was exacerbated by bicuculline and gabazine and reduced by isoguvacine. Thus in the model of high-K(+)/low Mg(2+)-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.
Section of Neurology, Dartmouth Medical School, Dartmouth-Hitchcock Medical School, Lebanon, NH 03756, USA.
Dmytro
D
Isaev
Elena
E
Isaeva
Rustem
R
Khazipov
Gregory L
GL
Holmes
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development; D066298:In Vitro Techniques; D007539:Isonicotinic Acids / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology*; D008274:Magnesium / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D011188:Potassium / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D012640:Seizures / Q000188:drug therapy; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018756:GABA Antagonists; D007539:Isonicotinic Acids; D008074:Lipoproteins; D011724:Pyridazines; C051928:lipoprotein-associated coagulation inhibitor; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; C049853:gabazine; D008274:Magnesium; D011188:Potassium; D001640:Bicuculline; C015300:isoguvacine