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Dopaminergic neurons inhibit striatal output through non-canonical release of GABA

Abstract

The substantia nigra pars compacta and ventral tegmental area contain the two largest populations of dopamine-releasing neurons in the mammalian brain. These neurons extend elaborate projections in the striatum, a large subcortical structure implicated in motor planning and reward-based learning. Phasic activation of dopaminergic neurons in response to salient or reward-predicting stimuli is thought to modulate striatal output through the release of dopamine to promote and reinforce motor action1,2,3,4. Here we show that activation of dopamine neurons in striatal slices rapidly inhibits action potential firing in both direct- and indirect-pathway striatal projection neurons through vesicular release of the inhibitory transmitter GABA (γ-aminobutyric acid). GABA is released directly from dopaminergic axons but in a manner that is independent of the vesicular GABA transporter VGAT. Instead, GABA release requires activity of the vesicular monoamine transporter VMAT2, which is the vesicular transporter for dopamine. Furthermore, VMAT2 expression in GABAergic neurons lacking VGAT is sufficient to sustain GABA release. Thus, these findings expand the repertoire of synaptic mechanisms used by dopamine neurons to influence basal ganglia circuits, show a new substrate whose transport is dependent on VMAT2 and demonstrate that GABA can function as a bona fide co-transmitter in monoaminergic neurons.

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Figure 1: DA neuron stimulation inhibits SPNs.
Figure 2: DA neurons directly release GABA onto SPNs.
Figure 3: GABA release from DA neurons requires VMAT2 but not VGAT.
Figure 4: VMAT2 functions as a vesicular GABA transporter.

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Acknowledgements

The authors thank A. Saunders and Y. Kozorovitskiy for generating and characterizing the AAV-DIO-EGFP and AAV-DIO-VGAT constructs, D. Sulzer and H. Zhang for assistance with amperometry, R. Shah and C. Johnson for technical support, and members of the laboratory for discussions. This work was supported by a Nancy Lurie Marks Family Foundation postdoctoral fellowship (N.X.T.) and by grants from the National Institutes of Health (NS046579 to B.L.S. and 4R00NS075136 to J.B.D.).

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N.X.T., J.B.D. and B.L.S. designed the experiments. N.X.T. performed the experiments described in the figures and text and analysed the data. J.B.D. performed experiments that initiated this study, devised the injection coordinates, established amperometric recordings and participated in their acquisition. N.X.T. and B.L.S. wrote the manuscript with contributions from J.B.D.

Corresponding author

Correspondence to Bernardo L. Sabatini.

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The authors declare no competing financial interests.

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Tritsch, N., Ding, J. & Sabatini, B. Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature 490, 262–266 (2012). https://doi.org/10.1038/nature11466

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