Overexpression of α–synuclein in Midbrain Dopamine Neurons Reduces Dopamine Release Without Cell Loss and Drives Mild Motor Deficits in Mice

It has proven challenging to faithfully recapitulate the key pathological, physiological, and behavioral features of Parkinson’s Disease (PD) in animals. Here we used adeno-associated virus (AAV) vectors to achieve cell type-specific overexpression of wild-type human α -synuclein ( α syn) and a fluorophore (mCherry) in midbrain dopamine neurons to model PD in mice. We found that AAVs drove selective expression of both α syn and mCherry in midbrain dopamine neurons. In conjunction with approximately 2-fold overexpression of α syn, we found several histopathological markers of PD-like pathology, including progressive accumulation of phosphorylated and aggregated α syn, ubiquitin, and a reduction in the expression of tyrosine hydroxylase, without overt cell loss. In parallel, α syn overexpression drove a profound loss of evoked dopamine release, without a substantive change in the intrinsic properties of dopamine neurons, nor in striatal dopamine content. Finally, α syn overexpression led to mild locomotor deficits. Together, these findings suggest that moderate α syn overexpression can mimic some aspects of premotor and early symptomatic phases of PD, including markers of Lewy Body-like pathology and functional loss of evoked dopamine release. This model may be useful for investigating cellular and circuit mechanisms related to PD pathogenesis and progression.