SUPPRESSED KINDLING EPILEPTOGENESIS AND PERTURBED BDNF AND TRKB GENE-REGULATION IN NT-3 MUTANT MICE

In the kindling model of epilepsy, repeated electrical stimulations le ad to progressive and permanent intensification of seizure activity. W e find that the development of amygdala kindling is markedly retarded in mice heterozygous for a deletion of the neurotrophin-3 (NT-3) gene (NT-3+/- mice). These mice did not reach the fully kindled state (3rd grade 5 seizure) until after 28 +/- 4 days of stimulation compared to 17 +/- 2 days in the wild-type animals. The deficit in the NT-3+/- mic e reflected dampening of the progression from focal to generalized sei zures. The number of stimulations required to evoke focal (grade 1 and 2) seizures did not differ between the groups, but the NT-3 mutants s pent a considerably longer period of time (13 +/- 3 days) than wild-ty pe mice (2 +/- 1 days) in grade 2 seizures. As assessed by test stimul ation 4-12 weeks after the 10th grade 5 seizure, kindling was maintain ed in the NT-3 mutants. In situ hybridization showed 30% reduction of basal NT-3 mRNA levels and lack of upregulation of TrkC mRNA expressio n at 2 h after a generalized seizure in dentate granule cells of the N T-3+/- mice, whereas the seizure-evoked increase in brain-derived neur otrophic factor (BDNF) and TrkB mRNA levels was enhanced. These result s indicate that endogenous NT-3 levels can influence the rate of epile ptogenesis, and suggest a link between NT-3 and BDNF gene regulation i n dentate granule cells. (C) 1997 Academic Press.