Midbrain dopamine (DA) neurons, a population of cells that are critical for motor control, motivated behaviors and cognition, release DA via an exocytotic mechanism from both their axonal terminals and their somatodendritic (STD) compartment. In Parkinson's disease (PD), it is striking that motor dysfunctions only become apparent after extensive loss of DA innervation. Although it has been hypothesized that this resilience is due to the ability of many motor behaviors to be sustained through a basal tone of DA and diffuse transmission, experimental evidence for this is limited. Here we conditionally deleted the calcium sensor synaptotagmin-1 (Syt1) in DA neurons (cKODA mice) to abrogate most activity-dependent axonal DA release in the striatum and mesencephalon, leaving STD DA release intact. Strikingly, Syt1 cKODA mice showed intact performance in multiple unconditioned DA-dependent motor tasks, suggesting that activity-dependent DA release is dispensable for such basic motor functions. Basal extracellular levels of DA in the striatum were unchanged, suggesting that a basal tone of extracellular DA is sufficient to sustain basic movement. We also found multiple adaptations in the DA system of cKODA mice, similar to those happening at early stages of PD. Taken together, our findings reveal the striking resilience of DA-dependent motor functions in the context of a near-abolition of phasic DA release, shedding new light on why extensive loss of DA innervation is required to reveal motor dysfunctions in PD.
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