In a study published in Cell Reports, Northwestern Medicine scientists rescued movement in a mouse model of Parkinson’s disease by restoring the intrinsic discharge of nerve cells within the subthalamic nucleus (STN), which is a component of the basal ganglia, a brain network critical for motor and impulse control.
In Parkinson’s disease, degeneration of dopamine-producing neurons in the brain causes the basal ganglia to develop abnormal, synchronized activity, which results in impaired motor function.
“We first determined the mechanisms that cause STN neurons to adapt to the loss of dopamine by slowing their autonomous pacemaking activity,” explained first author Eileen McIver, PhD, a medical writer and recent graduate of the Northwestern University Interdepartmental Neuroscience (NUIN) program.
The scientists found that elevated activity of the “indirect pathway” of the basal ganglia led to increased activation of STN glutamate receptors and ATP-sensitive potassium ion channels, which ultimately reduced autonomous firing. Furthermore, restoring this intrinsic activity with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) rescued motor function in a mouse model of Parkinson’s disease.
“Within ten minutes of injecting the designer drug to activate DREADDs in the STN, we saw a symptomatic improvement,” explained McIver.
“Our findings provide proof-of-concept for the use of tools like DREADDs as a therapeutic approach in Parkinson’s disease,” said McIver.
Mark Bevan, PhD, professor of Physiology, senior study author and McIver’s graduate advisor, commented, “Autonomous firing underlies the resting output of STN neurons and regulates their response to synaptic input. Dr. McIver’s study argues that the loss of this intrinsic activity promotes abnormal synchronization and motor dysfunction in Parkinson’s disease.”
Additional Northwestern study authors include D. James Surmeier, PhD, Nathan Smith Davis professor and chair of Physiology; David Wokosin, PhD, research associate professor of Physiology; Jeremy Atherton, PhD, and Jyothisri Kondapalli, PhD, research assistant professors of Physiology; and Hong-Yuan Chu, PhD, and Kathleen Cosgrove, PhD, postdoctoral fellows.
The study was supported by National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) grants 2R37 NS041280, P50 NS047085, 5T32 NS041234 and F31 NS090845. Confocal imaging work was performed at the Northwestern Center for Advanced Microscopy, supported by National Cancer Institute (NCI) Cancer Center Support Grant (CCSG) grant P30 CA060553.
