Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system

alpha-Synuclein (alpha-Syn) is a 14 kDa protein of unknown function that ha s been implicated in the pathophysiology of Parkinson's disease (PD). Here, we show that alpha-Syn(-/-) mice are viable and fertile, exhibit intact br ain architecture, and possess a normal complement of dopaminergic cell bodi es, fibers, and synapses. Nigrostriatal terminals of alpha-Syn(-/-) mice di splay a standard pattern of dopamine (DA) discharge and reuptake in respons e to simple electrical stimulation. However, they exhibit an increased rele ase with paired stimuli that can be mimicked by elevated Ca2+. Concurrent w ith the altered DA release, alpha-Syn(-/-) mice display a reduction in stri atal DA and an attenuation of DA-dependent locomotor response to amphetamin e. These findings support the hypothesis that alpha-Syn is an essential pre synaptic, activity-dependent negative regulator of DA neurotransmission.