Dysregulation of FGFR1 signaling in the hippocampus facilitates depressive disorder

Major depressive disorder (MDD) is a complex psychological disorder with a sophisticated molecular etiology. Although its connection with fibroblast growth factor receptor 1 (FGFR1) in the hippocampus is known, the precise mechanisms underlying its pathophysiology remain unclear. Here we conduct a comprehensive analysis of the molecular profile of the hippocampus in patients with MDD. We identified a distinct overexpression of FGFR1 specifically within the dentate gyrus of patients with MDD. Through the use of optogenetic techniques for the in vivo spatiotemporal dissection of FGFR1 signaling, we uncovered a sequential FGFR1-Notch-brain-derived neurotrophic factor (BDNF) pathway within the dentate gyrus, which can ultimately induce adult hippocampal neurogenesis, significantly contributing to antidepressant effects. We discovered that the dysregulation of this axis by the protein Numb, which demonstrates an age-related increase in individuals with MDD, is closely associated with the development of depressive phenotypes. Remarkably, targeting Numb to restore this axis effectively reversed the depressive phenotype, thus offering new insights into potential therapeutic strategies.