A dual role for α-synuclein in facilitation and depression of dopamine release from substantia nigra neurons in vivo

Significance We report a long-sought& in vivo& physiological role for& α-synuclein (α-syn) in dopamine signaling. The results indicate that& α-syn is critical for activity-dependent dopamine plasticity, and that short repeated burst activity produces rapid presynaptic facilitation, while prolonged burst activity slowly depresses evoked dopamine release. We propose that the rapid facilitation is due to an enhanced fusion of synaptic vesicles at active zones during exocytosis while the depression is due to synaptic exhaustion. These results identify a& dynamic role of& α-syn, and are critical for defining& molecular mechanisms and therapeutic targets for various neurological disorders, where the firing properties of neurons are severely altered.
α-Synuclein is expressed at high levels at presynaptic terminals, but defining its role in the regulation of neurotransmission under physiologically relevant conditions has proven elusive. We report that, in vivo, α-synuclein is responsible for the facilitation of dopamine release triggered by action potential bursts separated by short intervals (seconds) and a depression of release with longer intervals between bursts (minutes). These forms of presynaptic plasticity appear to be independent of the presence of β- and γ-synucleins or effects on presynaptic calcium and are consistent with a role for synucleins in the enhancement of synaptic vesicle fusion and turnover. These results indicate that the presynaptic effects of α-synuclein depend on specific patterns of neuronal activity.