Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice

Synaptotagmin 1 is involved in dopamine release. Here the authors investigate the effect of loss of Syt1 in midbrain dopaminergic neurons in mice, and find that unconditioned motor behaviour and motivation for food, are intact. In Parkinson's disease (PD), motor dysfunctions only become apparent after extensive loss of DA innervation. This resilience has been hypothesized to be due to the ability of many motor behaviors to be sustained through a diffuse basal tone of DA; but experimental evidence for this is limited. Here we show that conditional deletion of the calcium sensor synaptotagmin-1 (Syt1) in DA neurons (Syt1 cKO(DA) mice) abrogates most activity-dependent axonal DA release in the striatum and mesencephalon, leaving somatodendritic (STD) DA release intact. Strikingly, Syt1 cKO(DA) mice showed intact performance in multiple unconditioned DA-dependent motor tasks and even in a task evaluating conditioned motivation for food. Considering that basal extracellular DA levels in the striatum were unchanged, our findings suggest that activity-dependent DA release is dispensable for such tasks and that they can be sustained by a basal tone of extracellular DA. 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.

Automated summary

The authors investigated the effect of loss of SYT1 in midbrain dopaminergic neurons in mice, and found that unconditioned motor behavior and motivation for food are intact. This suggests that activity-dependent dopamine release is dispensable for these tasks, which can be sustained by basal dopamine levels.