The basal ganglia (BG) are a collection of interconnected subcortical nuclei that participate in a great variety of functions, ranging from motor programming and execution to procedural learning, cognition, and emotions. This network is also the region primarily affected by the degeneration of midbrain dopaminergic neurons localized in the substantia nigra pars compacta (SNc). This degeneration causes cellular and synaptic dysfunctions in the BG network, which are responsible for the appearance of the motor symptoms of Parkinson’s disease. Dopamine (DA) modulation and the consequences of its loss on the striatal microcircuit have been extensively studied, and because of the discrete nature of DA innervation of other BG nuclei, its action outside the striatum has been considered negligible. However, there is a growing body of evidence supporting functional extrastriatal DA modulation of both cellular excitability and synaptic transmission. In this review, the functional relevance of DA modulation outside the striatum in both normal and pathological conditions will be discussed.

Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key network within the basal ganglia. r In Parkinson's disease and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. r Using cell class-specific optogenetic identification and inhibition during cortical slow-wave activity and activation, we report that, in dopamine-depleted mice, (1) D2 dopamine receptor expressing striatal projection neurons (D2-SPNs) discharge at higher rates, especially during cortical activation, (2) prototypic parvalbumin-expressing GPe neurons are excessively patterned by D2-SPNs even though their autonomous activity is upregulated, (3) despite being disinhibited, STN neurons are not hyperactive, and (4) STN activity opposes striatopallidal patterning. r These data argue that in parkinsonian mice abnormal, temporally offset prototypic GPe and STN neuron firing results in part from increased striatopallidal transmission and that compensatory plasticity limits STN hyperactivity and cortical entrainment.

The external globus pallidus (GP) is a key GABAergic hub in the basal ganglia (BG) circuitry, a neuronal network involved in motor control. In Parkinson's disease (PD), the rate and pattern of activity of GP neurons are profoundly altered and contribute to the motor symptoms of the disease. In rodent models of PD, the striato-pallidal pathway is hyperactive, and extracellular GABA concentrations are abnormally elevated in the GP, supporting the hypothesis of an alteration of neuronal and/or glial clearance of GABA. Here, we discovered the existence of persistent GABAergic tonic inhibition in GP neurons of dopamine-depleted (DD) rodent models. We showed that glial GAT-3 transporters are downregulated while neuronal GAT-1 function remains normal in DD rodents. Finally, we showed that blocking GAT-3 activity in vivo alters the motor coordination of control rodents, suggesting that GABAergic tonic inhibition in the GP contributes to the pathophysiology of PD.