BDNF AND HIPPOCAMPAL HYPEREXCITABILITY

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DESCRIPTION: (Applicant's abstract) Brain-derived neurotrophic factor (BDNF) promotes growth and survival of several types of neurons in diverse systems. In addition, BDNF has been shown to enhance excitatory synaptic transmission in culture and in brain slices. In the hippocampus, BDNF staining is strongest in the mossy fiber axons of dentate gyrus granule cells, which innervate area CA3 pyramidal cells. We have recently found that exposure to BDNF enhances granule cell excitation of area CA3 pyramidal cells in hippocampal slices. Under these conditions, repetitive stimulation of granule cells can lead to epileptiform behavior in are CA3. These effects are selective in that excitation by other inputs are not enhanced. All effects are blocked by a nonspecific tyrosine kinsase inhibitor of trkB, the receptor that is thought to mediate BDNF's effects. The proposed studies will address whether the effects of BDNF are due to increased excitation or reduced inhibition. They will address whether BDNF's site of action is pre- or postsynaptic. The potential contribution of BDNF to hyperexcitability will be addressed, based on the above observations, and that BDNF message, protein, and receptor are increased by seizures. We predict that this induction increases BDNF's potential actions after seizures, and could contribute to the repetitive nature of seizures in chronic epilepsy. BDNF may also contribute to seizures after "sprouting," because mossy fibers form novel synapses in the dentate gyrus under these conditions. Because sprouting occurs in several animal models of epilepsy, and in many temporal lobe epileptics, these studies have implications for understanding the factors contributing to epileptogenesis. Finally, we will address the possible causal link between BDNF and excitotoxicity, a link suggested by the fact that several vulnerable subpopulations are targets of BDNF- immunoreactive fibers, but resistant cells are not. These studies will establish how an endogenous neurotrophin, considered to be neuroprotective primarily, can influence normal and abnormal activity in the limbic system.