Given the role of EphA4-ephexin1 signaling in the dendritic spine morphology25, 40, these findings suggest that EphA4-ephexin1 signaling might play a key role in the pathophysiology of depression, and the antidepressant-like effect of rhynchophylline might be at least in part due to an impairment of ephrin reverse signaling. This evidence concerns the gene NGEF and major depressive disorder.