Abstract

Significance Elevated expression of the presynaptic protein α-synuclein underlies familial and sporadic Parkinson disease (PD). However, our understanding of how increases in α-synuclein levels drive the sequence of events leading to PD is incomplete. Here, we apply a multidisciplinary longitudinal analysis to a new α-synuclein transgenic mouse model. We show that early-stage decreases in dopamine release and vesicle reclustering precede late-stage changes in neuronal firing properties, measured by in vivo recordings from vulnerable neurons. Accumulated deficits in dopamine neurotransmission and altered neuronal firing are associated with cell death and motor abnormalities, in the absence of protein aggregation in the substantia nigra. These findings have important implications for developing therapies.