Parkinson disease is well described at end-stage in postmortem studies, but there remains a need to define early functional changes in susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand these sequences of events, Janezic and colleagues generated transgenic mice that expressed wild-type α-synuclein at disease-relevant levels and displayed a transgene expression profile that recapitulated that of endogenous α-synuclein. The mice displayed age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype was preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits were not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits were associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged mice also exhibited reduced firing of SNc dopamine neurons in vivo. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting that neurophysiological changes preceded, but were not driven by, aggregate formation. This longitudinal phenotyping strategy provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.
Janezic S, Threlfell S, Dodson PD, Dowie MJ, Taylor TN, Potgieter D, Parkkinen L, Senior SL, Anwar S, Ryan B, Deltheil T, Kosillo P, Cioroch M, Wagner K, Ansorge O, Bannerman DM, Bolam JP, Magill PJ, Cragg SJ, Wade-Martins R: Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc. Natl. Acad. Sci. USA [Epub ahead of print, Sept. 30, 2013].
