Differential remodeling of subthalamic projections to basal ganglia output nuclei and locomotor deficits in 6-OHDA-induced hemiparkinsonian mice

Abstract

The subthalamic nucleus (STN) controls basal ganglia outputs via the substantia nigra pars reticulata (SNr) and the globus pallidus internus (GPi). However, the synaptic properties of these projections and their roles in motor control remain unclear. We show that the STN-SNr and STN-GPi projections differ markedly in magnitude and activity-dependent plasticity despite the existence of collateral STN neurons projecting to both the SNr and GPi. Stimulation of either STN projection reduces locomotion; in contrast, inhibition of either the STN-SNr projection or collateral STN neurons facilitates locomotion. In 6-OHDA-hemiparkinsonian mice, the STN-SNr projection is dramatically attenuated, but the STN-GPi projection is robustly enhanced; apomorphine inhibition of the STN-GPi projection through D2 receptors is significantly augmented and improves locomotion. Optogenetic inhibition of either the STN-SNr or STN-GPi projection improves parkinsonian bradykinesia. These results suggest that the STN-GPi and STN-SNr projections are differentially involved in motor control in physiological and parkinsonian conditions.