Hippocampal F3/Contactin plays a role in chronic stress-induced depressive-like effects and the antidepressant actions of vortioxetine in mice

Abstract

Depression is a very prevalent psychiatric disorder which threats nearly one in six of the population in this world. To date, the pathogenesis of depression remains elusive and is thought to depend on multiple factors in which chronic stress is critical. Currently, it has been demonstrated that besides monoaminergic dysfunction, depression is accompanied by several other important pathological phenomena such as impaired neurogenesis and decreased brain-derived neurotrophic factor (BDNF)-cAMP response element binding protein (CREB) signaling cascade in the hippocampus. F3/Contactin is a cell-adhesion molecule which has been reported to correlate with hippocampal neurogenesis and BDNF-CREB signaling. Here we assumed that F3/Contactin may be implicated in depression, and various methods including western blotting, immunofluorescence, virus-mediated gene transfer and chronic stress models of depression were adopted together. It was found that both chronic restraint stress (CRS) and chronic social defeat stress (CSDS) significantly decreased the expression of F3/Contactin in the hippocampus. Adeno-associated virus (AAV)-mediated over-expression of hippocampal F3/Contactin notably prevented the CRS-induced and CSDS-induced depressive-like behaviors in mice. Moreover, hippocampal F3/Contactin over-expression also fully reversed the CRS-induced and CSDS-induced dysfunction in the hippocampal BDNF-CREB signaling and neurogenesis of mice. Furthermore, administration of vortioxetine, a multimodal-acting antidepressant, fully ameliorated the inhibitory actions of both CRS and CSDS on the hippocampal F3/Contactin expression. In contrast, AAV-mediated knockdown of hippocampal F3/Contactin significantly abolished the protecting effects of vortioxetine against CRS and CSDS. Collectively, hippocampal F3/Contactin is implicated in depression and could be a novel antidepressant target.

Keywords: Brain-derived neurotrophic factor; Depression; Hippocampus, F3/Contactin; Neurogenesis; Vortioxetine; cAMP response element-binding protein.