Northwestern University Feinberg School of Medicine

Department of Physiology

Udall Center Research

Director: D. James Surmeier, PhD

Rhythmicity and Synchrony in the Basal Ganglia

Central Structure

The Northwestern University Udall Center brings together four principal investigators (PIs) from two research institutions (Northwestern University and University of Texas) with complementary expertise. The Center is directed by Dr. D. James Surmeier (Northwestern University). Project leaders are Drs. Surmeier, Mark Bevan (Northwestern University), Savio Chan (Northwestern University) and Charles Wilson (University of Texas, San Antonio). In addition to these research teams, the Center has an Administrative Core to coordinate activities of the projects and a Molecular Core to serve the genetic profiling and gene therapy aims of the projects.

Central Theme

Our Center is focused on two major lines of study in Parkinson’s disease (PD) with strong translational potential. The first line of study focuses on the mechanisms underlying the pathological rhythmic bursting activity patterns in the basal ganglia network formed by the subthalamic nucleus (STN), the external segment of the globus pallidus (GP) and the substantia nigra pars reticulate (SNr). This activity is thought to be responsible for the motor symptoms of PD. Our group has identified adaptations in the STN-GP-SNr network in PD models that could be responsible for this pathological activity. Our research teams are pursuing these discoveries and will attempt to translate it into new therapeutic approaches for late stage PD patients.

Our center is also focused on the causes of PD in the hope of developing disease modifying therapies. This effort has focused on the factors underlying selective vulnerability of dopaminergic neurons in the substantia nigra pars compacta (SNc), whose death in PD is responsible for akinesia, bradykinesia and rigidity. These studies led to the recognition that autonomous activity and the engagement of voltagegated calcium channels created a basal mitochondrial stress in at-risk SNc dopaminergic neurons, increasing their vulnerability to genetic mutations and environmental toxins. Importantly, these studies also suggest that vulnerability can be diminished with a drug that is approved for human use, an inference supported by epidemiological studies. These observations led to an NINDS-supported Phase III clinical trial in early stage PD patients with the drug isradipine that will be completed in 2018. While continuing our effort to understand how these intrinsic mechanisms, as well as synaptic mechanisms, contribute to pathogenesis, we have also initiated efforts to identify new and more powerful disease modifying drugs that lack significant side-effects. More recently, our team has expanded our study of pathogenesis to pursue the linkage between psychostimulant use and PD risk. This effort has uncovered an unexpected connection between mitochondria, calcium and dopamine in the axon terminals of SNc dopaminergic neurons that might drive terminal degeneration with prolonged psychostimulant use. This work also has identified a strategy for alleviating degeneration with FDA approved drugs.

Recent Significant Advances