Understanding the cellular and molecular mechanisms of limbic epileptogenesis may provide novel therapeutic targets for the prevention of epilepsy. The neurotrophins are a family of neuronal growth factors which have been implicated in epileptogenesis and represent emerging target molecules for the prevention of epilepsy. We hypothesize that brain-derived neurotrophic factor (BDNF) release and activation of its high affinity receptor tyrosine kinase, TrkB, is required for epileptogenesis. We predict the requirement of TrkB is independent of its well studied role as a mediator of neuronal development and we propose that one site at which TrkB activation is required for epileptogenesis is the dentate granule cells of the hippocampus. Our first specific aim is to generate a bacterial artificial chromosome (BAG) transgenic mouse where a cell-type specific promoter drives the expression of a Cre recombinase fused to the ligand binding domain of a mutant estrogen receptor (Cre-ER). These Cre-ER mice will be mated with TrkB floxed mice to generate Cre-ER/TrkB-floxed mice. Our final specific aim is to test if tamoxifen induced excision of TrkB from dentate granule cells is sufficient to prevent epileptogenesis in the kindling model of epilepsy.
| Soren Leonard, A; Puranam, Ram S; Helgager, Jeffrey et al. (2012) Conditional deletion of TrkC does not modify limbic epileptogenesis. Epilepsy Res 102:126-30 |
