Glutamate co-release from inhibitory nigral neurons reverses motor deficits in a Parkinson’s disease mouse model

Abstract Degeneration of midbrain dopamine neurons in Parkinson’s disease increases inhibitory output from the basal ganglia, including from GABAergic neurons of the substantia nigra pars reticulata (SNr), thereby suppressing thalamocortical drive and impairing movement. Whether altering the transmitter output of these inhibitory neurons can restore circuit function remains unknown. Here, we genetically reprogrammed mouse SNr GABAergic neurons to co-release glutamate by Cre-dependent expression of the vesicular glutamate transporter VGLUT2. VGLUT2 expression was both necessary and sufficient to induce glutamate co-release and activate postsynaptic glutamate receptors in thalamic target neurons. In a mouse model of unilateral dopamine depletion, ectopic VGLUT2 expression robustly restored motor performance. These findings demonstrate that basal ganglia output neurons retain the capacity for functional transmitter reconfiguration and that inducing glutamate co-release in SNr GABA neurons can reverse pathological motor deficits resulting from dopamine denervation.