Brain-derived neurotrophic factor infusion delays amygdala and perforant path kindling without affecting paired-pulse measures of neuronal inhibitionin adult rats

Kindling is an animal model of human temporal lobe epilepsy in which excita bility in limbic structures is permanently enhanced by repeated stimulation s. Kindling also increases the expression of nerve growth factor, brain-der ived neurotrophic factor, and brain-derived neurotrophic factor receptor me ssenger RNAs in both the hippocampus and cerebral cortex and causes structu ral changes in the hippocampus including hilar hypertrophy. We have recentl y shown that intraventricular nerve growth factor infusion enhances the dev elopment of kindling, whereas blocking nerve growth factor activity retards amygdaloid kindling. Furthermore, we have shown that nerve growth factor p rotects against kindling-induced hilar hypertrophy. The physiological role of brain-derived neurotrophic factor in kindling is not as clear. Acute inj ection of brain-derived neurotrophic factor increases neuronal excitability and causes seizures, whereas chronic brain-derived neurotrophic factor inf usion in rats slows hippocampal kindling. In agreement with the latter, we show here that intrahilar brain-derived neurotrophic factor infusion delays amygdala and perforant path kindling. In addition, we show that brain-deri ved neurotrophic factor, unlike nerve growth factor, does not protect again st kindling-induced increases in hilar area. To test the hypothesis that br ain-derived neurotrophic factor suppresses kindling by increasing inhibitio n above normal levels, we performed paired-pulse measures in the perforant path-dentate gyrus pathway. Brain-derived neurotrophic factor infused into the hippocampus had no effect on the stimulus intensity function (input/out put curves); there was also no significant effect on paired-pulse inhibitio n. We then kindled the perforant path 10 days after the end of brain-derive d neurotrophic factor treatment. Once again, kindling was retarded, showing that the brain-derived neurotrophic factor effect is long-lasting. These results indicate that prolonged in vivo infusion of brain-derived neu rotrophic factor reduces, rather than increases, excitability without incre asing inhibitory neuron function, at least as assessed by paired-pulse prot ocols. This effect may be mediated by long-lasting effects on brain-derived neurotrophic factor receptor regulation. (C) 1999 IBRO. Published by Elsev ier Science Ltd.