Dr. Francis Lee’s laboratory has focused understanding the molecular basis of neuropsychiatric disorders including depression and anxiety disorders through a ”bottom up” strategy, combining cell biological techniques with genetically altered mouse studies. His current research has centered on a unique family of growth factors, neurotrophins, which have profound effects on neuronal survival and synapse formation in neural circuits. His laboratory has recently focused on common human genetic variant in the neurotrophin, brain derived neurotrophic factor (BDNF) that leads to a single amino acid change in the BDNF protein (Val66Met). His laboratory has determined that the molecular defect in variant BDNF relates to its aberrant trafficking to secretory pathways in neurons due to abnormal engagement with VPS10 domain sorting proteins. The laboratory subsequently generated a knock-in mouse containing this human variant BDNF to study the in vivo consequences of this secretion defective BDNF, and elucidated a phenotype that had not been established in humans: increased anxiety. The form of anxiety elicited in these mice was not responsive to a common SSRI, and suggests that humans with this allele may not have optimal responses to this class of antidepressants. The variant BDNF mouse may thus serve as a valuable model to study in a more precise manner the contribution of human genetic variants to neuropsychiatric disorders, as well as identify novel pharmacologic approaches to treating these disorders.