GRANULE CELL DISINHIBITION IN DENTATE GYRUS OF GENETICALLY SEIZURE-SUSCEPTIBLE EL MICE

Paired-pulse inhibition was investigated electrophysiologically in the dentate gyrus using hippocampal slices from epileptic El mice. At sho rt interpulse intervals (IPIs), the inhibition was 30% in the El, and 90% in the control ddY mice at the ages of 10 and 15 weeks. No differe nce in inhibition was observed at the age of 5 weeks. Bicuculline, a G ABA(A) receptor antagonist, attenuated the inhibition during short IPI s in the ddY mice, while in the El mice, phenobarbital and flunitrazep am, which enhance GABA(A) receptor function, restored the inhibitory a ctivity comparable to that of the ddY. The disinhibition progressed wi th growth, closely correlating with seizure development in El mice. Th ese results suggest that decrease in the GABAergic inhibition occurs i n the dentate gyrus of the El mice with growth. GABA concentration in the hippocampus was also quantified using HPLC. In El mice, GABA level was significantly lower than that in ddY mice at the ages of 5 and 15 weeks. Thus, the disinhibition observed in the El dentate gyrus at 15 weeks of age does not appear to be directly related to the content of GABA. GAB Aergic disinhibition suggests possible loss of unknown inhi bition control factor(s) in the El dentate gyrus as growth progresses. The growth-dependent disinhibition in the granule cells may be a prer equisite for epileptogenesis in EI mice.