Membrane fusion deficits of acutely isolated synaptic vesicles from the brains of depression-like mice.

Abstract

Depression is a common and debilitating psychiatric disorder increasingly associated with presynaptic dysfunction, particularly impairments in synaptic vesicle (SV)-mediated neurotransmitter release, yet its underlying neurobiological mechanisms remain largely unresolved. In this study, we investigated SV morphology and fusion capability in a chronic variable stress (CVS)-induced mouse model of depression. To enable this analysis, we established an optimized protocol integrating differential centrifugation, density gradient ultracentrifugation, and size exclusion chromatography to isolate high-purity SVs from mouse brain tissue. Behavioral analyses confirmed the depression-like phenotype in CVS mice, characterized by anhedonia, anxiety-like behavior and behavioral despair. Although SV morphology, as characterized by TEM, appeared largely preserved, reconstituted vesicle fusion assays demonstrated a significant decline in their fusion capacity, suggesting impaired neurotransmitter release. These findings provide direct evidence of functional SV alternations in depression and underscore the key role of presynaptic dysfunction in its pathophysiology. The optimized SV isolation workflow developed in this study offers a valuable tool for investigating presynaptic mechanisms in neuropsychiatric disorders.