Functional Analysis of Distinct Populations of Subthalamic Nucleus Neurons on Parkinson’s Disease and OCD-like Behaviors in Mice

ABSTRACT The Subthalamic Nucleus (STN) is a component of the basal ganglia and plays a key role to control movement and limbic-associative functions. STN modulation with Deep Brain Stimulation (DBS) improves the symptoms of Parkinson’s Disease (PD) and Obsessive-Compulsive Disorder (OCD) patients. However, DBS does not allow for cell-type specific modulation of the STN. While extensive work has focused on understanding STN functionality, the understanding of its cellular components is limited. Here, we first performed an anatomical characterization of molecular markers for specific STN neurons. These studies revealed that most STN neurons express Pitx2 , and that different overlapping subsets express Gabrr3 , Ndnf or Nos1 . Next, we used neuronal modulatory tools to demonstrate their roles in regulating locomotor and limbic functions in mice. Specifically, we showed that optogenetic photoactivation of STN neurons in Pitx2-Cre mice or of the Gabrr3-expressing subpopulation induces locomotor changes, and improves locomotion in a PD mouse model. Additionally, photoactivation of Pitx2 and Gabrr3 cells induced repetitive grooming, a phenotype associated with OCD. Repeated stimulation prompted a persistent increase in grooming that could be reversed by fluoxetine treatment, a first-line drug therapy for OCD. Conversely, repeated inhibition of STN Gabrr3 neurons suppressed grooming in Sapap3-KO mice, a model for OCD. Finally, circuit and functional mapping of STN Gabrr3 neurons showed that these effects are mediated via projections to the globus pallidus/entopeduncular nucleus and substantia nigra reticulata. Altogether, these data identify Gabrr3 neurons as a key population in mediating the beneficial effects of STN modulation thus providing a new molecular handle for PD and OCD drug discovery.