Functional alterations of the dopaminergic and glutamatergic systems in spontaneous α-synuclein overexpressing rats

Abstract The presence of α-synuclein (α-syn) in Lewy bodies and Lewy neurites is an important characteristic of the neurodegenerative processes of substantia nigra pars compacta (SNpc) dopaminergic (DAergic) neurons in Parkinson's disease (PD) and other synucleinopathies. Here we report that Berlin-Druckrey rats carrying a spontaneous mutation in the 3′ untranslated region of α-syn mRNA ( m/m rats) display a marked accumulation of α-syn in the mesencephalic area, striatum and frontal cortex, accompanied to severe dysfunctions in the dorsolateral striatum. Despite a small reduction in the number of SNpc and ventral tegmental area DAergic cells, the surviving dopaminergic neurons of the m/m rats do not show clear-cut alterations of the spontaneous and evoked firing activity, DA responses and somatic amphetamine-induced firing inhibition. Interestingly, mutant DAergic neurons display diminished whole-cell I h conductance and a reduced frequency of spontaneous excitatory synaptic currents. By contrast, m/m rats show a severe impairment of DA and glutamate release in the dorsolateral striatum, as revealed by amperometric measure of DA currents and by electrophysiological recordings of glutamatergic synaptic events in striatal medium spiny neurons. These functional impairments are paralleled by a decreased expression of the DA transporter and VGluT1 proteins in the same area. Thus, together with α-syn overload in the mesencephalic region, striatum and frontal cortex, the main functional alterations occur in the DAergic and glutamatergic terminals in the dorsal striatum of the m/m rats.