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

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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.

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