cgp-56999a and Epilepsy

Whether seizures in the developing brain cause long-term changes in the mature brain has been debated. We tested the hypothesis that a model of early-life seizures, induced by systemic injection of a GABA(B) receptor antagonist CGP56999A in immature rats, decreased GABA(B) receptor-mediated inhibitory postsynaptic currents (IPSCs) in the hippocampus of adolescent rats. Whole-cell recordings were made in CA1 pyramidal cells and dentate gyrus (DG) granule cells in vitro, 30-45 days after the rats had seizures induced by CGP56999A (1-1.5 mg/kg i.p.) or control saline injection on postnatal day 15. GABA(B) receptor-mediated IPSCs were reduced in DG neurons but not in CA1 neurons of early-life seizure rats as compared to controls. Additionally, hippocampal neurons of early-life seizure rats, as compared to those in control rats, showed a more depolarized resting membrane potential in both CA1 and DG, and a larger input resistance but reduced spike frequency adaptation in DG neurons. In conclusion, early-life seizures result in a long-lasting reduction in GABA(B) receptor-mediated transmission in DG principal neurons and depolarization in CA1 and DG principal neurons. These alterations are expected to increase seizure susceptibility in the adult brain.

Topics: Action Potentials; Age Factors; Aging; Animals; Animals, Newborn; CA1 Region, Hippocampal; Dentate Gyrus; Down-Regulation; Epilepsy; GABA Antagonists; GABA-B Receptor Antagonists; gamma-Aminobutyric Acid; Hippocampus; Inhibitory Postsynaptic Potentials; Male; Neural Inhibition; Neurons; Organ Culture Techniques; Patch-Clamp Techniques; Phosphinic Acids; Rats; Rats, Long-Evans; Receptors, GABA-B; Synapses; Synaptic Transmission; Time

The expression of secretogranin-II and its major proteolytic product secretoneurin (SN) is under the control of neuronal excitation, as demonstrated by treating rats with the excitotoxic kainic acid (KA). Differences in the structure and function of the hippocampus in rats and gerbils have been described; these suggest possible differential reactive responses to KA. In the present study, the SN immunostaining pattern in relation with cell damage is analyzed from 6 h to 4 days following KA administration in rats and gerbils. Dramatic differences in the expression of SN were found in the hippocampal complex following KA administration in gerbils and rats. A robust increase in SN immunoreactivity was detected in the pyramidal cell layer of the rat hippocampus, especially in the CA1 area. In the gerbil, however, a strong increase in SN immunostaining was detected in interneurons of the hippocampal formation, as shown by double-labeling immunohistochemistry to SN and the calcium-binding proteins parvalbumin, calbindin, and calretinin. In addition, no damage (in the hippocampal formation) or moderate damage (in the entorhinal cortex) was observed in the gerbil, in contrast to the rat. The administration of KA and the GABA-B receptor inhibitors (CGP56999A or CGP36742) to the gerbil resulted in a strong rise in SN immunoreactitivty in the CA1 pyramidal cell layer of the hippocampus, as in the rat. However, no increased cell damage was observed under these conditions. The present data provide evidence of a species-differential reactive response to KA that might be based, in part, on distinct inhibitory intrahippocampal circuitry.

Topics: Animals; Calbindin 2; Calbindins; Chromogranins; Convulsants; Epilepsy; Excitatory Amino Acid Agonists; GABA Antagonists; GABA-B Receptor Antagonists; Gerbillinae; Hippocampus; Immunohistochemistry; Kainic Acid; Neuropeptides; Organophosphorus Compounds; Parvalbumins; Phosphinic Acids; Proteins; Rats; Rats, Sprague-Dawley; S100 Calcium Binding Protein G; Secretogranin II