This proposal aims at studying the role of BDNF in cerebellar development. It examines the hypothesis that lack of BDNF might result in a epileptic and/or ataxic phenotype. The study takes advantage of a recently described genetic model with selective defect of BDNF in the cerebellum, the recessive single locus mutation stargazer (stg).The most striking features of this neurologic mutation are ataxia, episodic neck retroflexion, and severe generalized spike-wave seizures. It is proposed to characterize mRNA and protein levels of selected neurotrophins and neurotrophin receptors in the cerebellum of stargazer. Further, using intracerebral infusion of BDNF in developing stargazer mice, it will be attempted to reverse or attenuate the observed functional deficits and the cerebellar atrophy observed in the mutant mice. If confirmed to be virtually free of BDNF protein, the stargazer cerebellum will be used to study the effects of chronic treatment with BDNF on the responsiveness of the BDNF receptor. The proposed experiments may ultimately lead to new insights into the roles of neurotrophic factors during brain development and, possibly, into causes and consequences of epileptic seizure activity in the brain. They might also provide information relevant to trophic actor treatment in neurological diseases.
