This proposal aims at studying the role of BDNF in cerebellar development. It examines the hypothesis that lack of BDNF might result in an 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. I have completed characterization of mRNA levels of selected neurotrophins and neurotrophin receptors in the cerebellum of stargazer, and evaluation of the deficiencies in moor coordination and cerebellar learning of this mutant. To study the effect of BDNF, I have been examining the morphology of stg cerebellum during the development at the light microscope level, and found delayed granule cell migration at P15. I am setting up to expand the study to the EM level. Based on our recent finding of glutamate receptor transmission defect in stg cerebellum, I propose to examine the glutamate receptor expression levels and study the relationship between the neurotrophic factor BDNF and glutamate neurotransmission. Further, crossbreeding of stargazer with a BDNF over expressing transgenic mouse is proposed to directly test for involvement of BDNF in the observed symptoms. Together, 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 ataxia and epileptic seizure activity in the brain. They might also provide information relevant to trophic factor treatment in neurological diseases.
