Nuclear localization of alpha-synuclein induces anxiety-like behavior in mice by decreasing hippocampal neurogenesis...

Fear and anxiety are common in Parkinson's disease (PD) and may be caused by pathologies outside the dopaminergic system. Increasing evidence has shown that alpha-synuclein (α-syn) is involved in the development of anxiety in PD. In this study, we examined the effects of α-syn nuclear translocation on anxiety-like behavior in mice by overexpressing α-syn in the nuclei of the cell in the hippocampus. Our results show that α-syn overexpression in the nuclei increased the excitability of hippocampal neurons and activated NG2 glial cells and promoted the synthesis and release of γ-aminobutyric acid (GABA). And nuclear localization of α-syn led to the loss of neurotrophic factors and decreased neurogenesis. Meanwhile, the hippocampus and amygdala acted synergistically, resulting in pathologic accumulation of α-syn and gliosis in the amygdala and caused loss of interneurons. These events led to the impairments of hippocampus and amygdala function, which ultimately induced anxiety-like behavior in mice. The findings obtained in our present study indicate that excessive nuclear translocation of α-syn in hippocampal neurons and damage to the amygdala circuits may be important in the development of anxiety in PD.