Synaptotagmin-7 counteracts short-term depression during phasic dopamine release.

Dopamine neurons switch from tonic pacemaker activity to high-frequency bursts in response to salient stimuli. These bursts lead to superlinear increases in dopamine release, and the degree of this increase is highly dependent on firing frequency. The superlinearity and frequency-dependence of dopamine release implicates short-term plasticity processes. The presynaptic Ca2+ -sensor synaptotagmin-7 (SYT7) has suitable properties to mediate such short-term plasticity and has been implicated in regulating dopamine release from somatodendritic compartments . Here we use a genetically-encoded dopamine sensor and whole-cell electrophysiology in Syt7 knockout mice to determine how SYT7 contributes to both axonal and somatodendritic dopamine release. We find that SYT7 mediates a hidden component of facilitation of release from dopamine terminals that can be unmasked by lowering initial release probability, or by pre-depressing synapses with low-frequency stimulation. Depletion of SYT7 increased short-term depression and reduced release during stimulations that mimic in vivo firing. Recordings of D2-mediated inhibitory postsynaptic currents in the substantia nigra pars compacta (SNc) confirmed a similar role for SYT7 in somatodendritic release. Our results indicate that SYT7 drives short-term facilitation of dopamine release, which may explain the frequency-dependence of dopamine signaling seen in vivo Significance Statement Each midbrain dopamine neuron releases onto thousands of downstream cells, allowing the activity of dopamine neurons to exert outsized impacts on movement, motivation, and learning. Dopamine release scales non-linearly with firing rates, suggesting these neurons might employ classical mechanisms of activity-dependent plasticity. Here we show that dopamine release sites in multiple brain regions employ a well-characterized mechanism for plasticity, synaptotagmin-7, to dramatically boost dopamine release during high-frequency activity. This work generalizes a mechanism of short term-plasticity that has been well-characterized at conventional synapses to the release of neuromodulators, and helps to explain the activity-dependence of dopamine release.