GDNF attenuates a-synuclein aggregation-induced damage to VTA-NAc dopaminergic transmission and alleviates depression-like behaviors in mice.

Dopamine (DA) transmission from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is strongly associated with depression in Parkinson's disease (PD). Decreased DA levels due to alpha-synuclein (α-syn) aggregation have been underappreciated in relation to depression in PD. This study investigated the role of VTA-related α-syn aggregation in depression of PD, and whether gial cell line-derived neurotrophic factor (GDNF) can inhibit α-syn aggregation to improve symptoms. Here, α-syn aggregation and GDNF overexpression were induced in the VTA of 8-week-old male mice (C57BL/6J, DAT-cre, D2-cre) using adeno-associated viruses, combined with a cis-tracer virus as well as a chemogenetic virus. Behavioral tests, immunofluorescence (IF), western blot (WB), and enzyme-linked immunosorbent assay (ELISA) were employed for analysis. The mice with increased p-α-syn in VTA exhibited depressive-like behavior, along with reduced DA levels in the VTA and NAc, as well as reduced expression of related proteins in the NAc. However, GDNF overexpression in the VTA, led to a decrease in p-α-syn expression and reversed the aforementioned phenomena. Furthermore, results from cis-tracer virus and Immunofluorescence (IF) assay revealed a reduction in transmission of DA from the VTA to the NAc in mice with α-syn aggregation, which can be reversed by GDNF overexpression. Additionally, chemogenetic virus-induced diminished D2-MSN activation in the NAc significantly ameliorated depression-like behavior due to α-syn aggregation in the VTA. In conclusion, the aggregation of α-syn within the VTA may contribute to depression in PD, while GDNF can alleviate depression by inhibiting α-syn aggregation.