FBXL20 promotes synaptic impairment in depression disorder via degrading vesicle-associated proteins

Abstract

BackgroundSynaptic plasticity changes in presynaptic terminals or postsynaptic membranes play a critical role in cognitive impairments and emotional disorders, but the underlying molecular mechanisms in depression remain largely unknown. MethodsThe regulation effects of F-box and leucine-rich repeat protein 20 (FBXL20), vesicular glutamate transporter 1 (VGLUT1) and vesicle-associated membrane protein 1 (VAMP1) on synaptic plasticity and depressive-like behaviors examined by proteomics analysis, viral stereotaxic injection, transmission electron microscope and biochemical methods. The glutamate release detected by fluorescent probe in cultured primary pyramidal neurons. ResultsWe found that chronic unpredictable mild stress (CUMS) induced significant synaptic deficits within hippocampus of depressed rats, accompanied with the decreased expression of VGLUT1 and VAMP1. Moreover, knockdown of VGLUT1 or VAMP1 in hippocampal pyramidal neurons resulted in abnormal glutamatergic neurotransmitter release. In addition, we found that the E3 ubiquitin ligase FBXL20 was increased within hippocampus, which may promote ubiquitination and degradation of VGLUT1 and VAMP1, and thus resulted in the reduction of glutamatergic neurotransmitter release, the disruptions of synaptic transmission and the induction of depression-like behaviors in rats. In contrast, shRNA knockdown of FBXL20 within the hippocampus of depressed rats significantly ameliorated synaptic damage and depression-like behaviors. LimitationOnly one type of depression model was used in the present study, while other animal models should be used in the future to confirm the underlying mechanisms reported here. ConclusionsThis study provides new insights that inhibiting FBXL20 pathway in depressed rats may be an effective strategy to rescue synaptic transmission and depression-like behaviors.