Maladaptive Downregulation of Autonomous Subthalamic Nucleus Activity following the Loss of Midbrain Dopamine Neurons

Abnormal subthalamic nucleus (STN) activity is linked to impaired movement in Parkinson’s disease (PD). The autonomous firing of STN neurons, which contributes to their tonic excitation of the extrastriatal basal ganglia and shapes their integration of synaptic input, is downregulated in PD models. Using electrophysiological, chemogenetic, genetic, and optical approaches, we find that chemogenetic activation of indirect pathway striatopallidal neurons downregulates intrinsic STN activity in normal mice but this effect is occluded in Parkinsonian mice. Loss of autonomous spiking in PD mice is prevented by STN N-methyl-D-aspartate receptor (NMDAR) knockdown and reversed by reactive oxygen species breakdown or KATP channel inhibition. Chemogenetic activation of hM3D(Gq) in STN neurons in Parkinsonian mice rescues their intrinsic activity, modifies their synaptic integration, and ameliorates motor dysfunction. Together these data argue that in PD mice increased indirect pathway activity leads to disinhibition of the STN, which triggers maladaptive NMDAR-dependent downregulation of autonomous firing. [Display omitted] •Autonomous subthalamic nucleus (STN) activity is downregulated after loss of dopamine•Elevated D2-striatal projection neuron transmission is sufficient for downregulation•Downregulation is dependent on activation of STN NMDA receptors and KATP channels•Chemogenetic restoration of autonomous spiking reduces Parkinsonian dysfunction in mice McIver et al. describe the cellular and circuit mechanisms responsible for the loss of autonomous subthalamic nucleus (STN) spiking in dopamine-depleted mice and demonstrate that chemogenetic rescue of intrinsic STN activity reduces Parkinsonian motor dysfunction.