Tonic dendritic GABA release by substantia nigra dopaminergic neurons

Recent studies have demonstrated the importance of extrastriatal dopamine release in the emergence of the network dysfunction underlying motor deficits in Parkinsons disease (PD). To better characterize the actions of dopamine on substantia nigra pars reticulata (SNr) GABAergic neurons, optogenetic and electrophysiological tools were used in ex vivo mouse brain slices to monitor synaptic transmission arising from globus pallidus externa (GPe) neurons. As predicted by previous work, activation of D2 dopamine receptors (D2Rs) suppressed GABA release evoked by stimulation of GPe axons. However, D2R activation also suppressed a tonic, GABAA receptor-mediated inhibition of SNr spiking. D2R-mediated inhibition of tonic GABA release led to a roughly 30% increase in SNr spiking rate. Chemogenetic inhibition of GPe terminals or excitation of astrocytes did not affect tonic GABA release in the SNr. In contrast, chemogenetic inhibition of dopaminergic neurons or knocking down the expression of aldehyde dehydrogenase 1A1 (ALDH1A1) blunted tonic GABAergic signaling. Antagonizing D1 dopamine receptors on the terminals of striatonigral neurons also modestly increased SNr spiking. Lastly, in a progressive mouse model of PD targeting dopaminergic neurons, the tonic inhibition of SNr neurons by GABA release also was lost. Taken together, these observations suggest that dopamine and GABA are co-released by the dendrites of ALDH1A1-expressing dopaminergic neurons that course through the SNr. The co-release of these transmitters could serve to promote movement by making SNr neurons less responsive to phasic activity arising from the indirect pathway circuitry and by lowering basal spiking rates.