Understanding partial epileptogenesis in cellular and molecular terms may provide clues for developing effective preventive therapies. Our preliminary studies reveal that a specific subtype of neurotrophin receptor, TrkB, is required for epileptogenesis in the kindling model. The objectives of this proposal are to begin to explore the mechanisms by which absence of TrkB limits epileptogenesis and to further evaluate TrkB as a potential target for anti-epileptogenic therapies. These objectives will be accomplished by study of genetically modified mice with biochemical, anatomic, and electrophysiological methods. We propose four Aims. To examine the dendritic structure and synaptic physiology of dentate granule cells in TrkB -/- and WT mice. To examine the development of amygdala kindling in mice in which TrkB signaling is inhibited de novo in the postnatal brain. To examine the effect of inhibition of TrkB signaling on persistence of hyperexcitability in the kindling model. To examine the effects of inhibiting TrkB signaling on limbic epileptogenesis and mossy fiber sprouting of the granule cells in multiple models. Successful completion of these Specific Aims could establish TrkB and its signaling pathways as highly attractive molecular targets for development of pharmacologic agents for prevention of epilepsy.
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