Mechanisms of BDNF as a neurotrophic factor

Through a ”bottom up” approach involving cell biological and genetically altered mouse studies, we consider the molecular basis and in vivo consequences of a common human genetic variant in the growth factor, BDNF. We have previously identified a sorting mechanism involving unique sequence elements in the BDNF prodomain, as well as a sorting protein, sortilin that specifically mediates this trafficking decision to the regulated secretory pathway.  This sortilin-BDNF interaction provides a plausible molecular model of understanding the trafficking defect found in the common human genetic variant BDNF (Val66Met). We have also generated a knock-in mouse containing the BDNF SNP that represents the first example of a human SNP that has been modeled in mice. This was the one of the first animal models to recapitulate the phenotypic effects of a common human polymorphism expressed in the brain. Analyses of this mouse model have elucidated additional phenotypes (increased anxiety, altered fear learning) and have led to these phenotypes being identified in humans.