Parkinson's disease (PD) is a
neurodegenerative disorder characterized by a progressive loss of nigral dopaminergic neurons and by the presence of aggregates containing α-
synuclein called Lewy bodies. Viral vector-induced overexpression of α-
synuclein in dopaminergic neurons represents a model of PD which recapitulates
disease progression better than commonly used
neurotoxin models. Previous studies using this model have reported motor and
cognitive impairments, whereas depression, mood and anxiety phenotypes are less described. To investigate these psychiatric phenotypes, Sprague-Dawley rats received bilateral
injections of a recombinant adeno-associated virus (AAV) vector expressing human α-
synuclein or GFP into the substantia nigra pars compacta. Behavior was assessed at two timepoints: 3 and 8 weeks post-injection. We report that nigral α-
synuclein overexpression led to a pronounced nigral dopaminergic cell loss accompanied by a smaller cell loss in the ventral tegmental area, and to a decreased striatal density of dopaminergic fibers. The AAV-α-
synuclein group exhibited modest, but significant motor impairments 8 weeks after vector administration. The AAV-α-
synuclein group displayed depressive-like behavior in the forced swim test after 3 weeks, and reduced
sucrose preference at week 8. At both timepoints, overexpression of α-
synuclein was linked to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis regulation of
corticosterone. The depressive-like phenotype was also correlated with decreased nigral
brain-derived neurotrophic factor and
spinophilin levels, and with decreased striatal levels of the activity-regulated cytoskeleton-associated
protein. This study demonstrates that AAV-mediated α-
synuclein overexpression in dopamine neurons is not only useful to model motor impairments of PD, but also depression. This study also provides evidence that depression in
experimental Parkinsonism is correlated to dysregulation of the HPA axis and to alterations in
proteins involved in synaptic plasticity.