The synaptic vesicle priming protein Munc13 mediates evoked somatodendritic dopamine release

Midbrain dopamine neurons release dopamine not only from their axons, but also from their somata and dendrites. Shared and distinct properties have been proposed for somatodendritic and axonal release, but the mechanisms of somatodendritic release remain unclear. We here used gene knockout, electrophysiology, and imaging to define roles of the synaptic vesicle priming protein Munc13 in somatodendritic dopamine release in comparison to axonal secretion. We characterized mice of either sex and found that Munc13 ablation decreased evoked but not spontaneous somatodendritic dopamine transmission measured as D2 receptor-mediated currents. Imaging with a fluorescent sensor confirmed the importance of Munc13 in evoked somatodendritic and axonal dopamine secretion. Pharmacological experiments revealed a modest contribution of release from norepinephrine axons to D2 receptor-mediated currents, and the relative contribution was enhanced after Munc13 knockout. Altogether, these data establish important roles for Munc13 in evoked somatodendritic release. These roles are similar to Munc13 functions in axonal dopamine release and at fast synapses. Spontaneous midbrain dopamine release was not impaired by Munc13 ablation from dopamine neurons and may rely on a release pathway that is independent of the prototypical release machinery employed at synapses. Significance statement Neurons release neurotransmitter with high spatiotemporal precision from axonal nerve terminals. In addition, neurons also secrete transmitters such as monoamines, neurotrophins and neuropeptides from their somata and dendrites. While axonal release has been well characterized, less is known about mechanisms of somatodendritic secretion. The presented data establish that the synaptic vesicle priming protein Munc13 is important for evoked somatodendritic dopamine release. By contrast, spontaneous somatodendritic dopamine release is not affected by Munc13 ablation from dopamine neurons in the tested mouse mutants. The Munc13-dependence of evoked somatodendritic secretion supports the model of spatiotemporally precise signaling for this form of transmission. Spontaneous dopamine release may rely on a pathway that is independent of the classical neurotransmitter release machinery.