Hippocampal alpha-synuclein mediates depressive-like behaviors.

• SNCA is up-regulated in the peripheral blood of major depressive disorder patients and in the hippocampus of depressive mice. • SNCA overexpression in the hippocampus induces depressive-like behaviors in mice, while SNCA knockout has antidepressant effects. • SNCA in hippocampus leads to synapse loss and neuronal cell death involved in depressive-like behaviors probably via complement system. • Complement system may play a key role in pathogenesis and progression of depressive disorder via microglia-mediated engulfment of synapses during inflammation. Alpha-synuclein (α-syn) which encoded by SNCA plays a critical role in the neurotransmission, vesicle dynamics, and neuroplasticity. Alteration to SNCA expression is associated with major depressive disorder. However, the pathogenic mechanism of SNCA in depression remains unknown. Herein, we reported that SNCA was up-regulated in the peripheral blood of major depressive disorder (MDD) patients and the depressive mice. Chronic restraint stress (CRS) also up-regulated the SNCA expression in the hippocampus. Moreover, over-expression of SNCA in the hippocampus triggered spontaneous depressive-like behaviors under the non-stressed conditions in mice, and knockout of SNCA could reverse CRS-induced depressive-like behaviors. SNCA led to synapse loss and neuronal cell death in the hippocampus possibly via complement-mediated microglial engulfment and inflammation, and thus contributed to the pathogenesis of depressive disorder. Overall, hippocampal SNCA and complement system are involved in the pathogenesis of depressive disorder and it provides a new perspective for the occurrence of depressive disorder. [ABSTRACT FROM AUTHOR]