Northwestern Medicine scientists have discovered that targeting neuronal signaling controlling aberrant learning in the striatum may improve the efficacy of a first-line therapy for Parkinson’s disease and has the potential to reduce therapy-related side effects, according to a recent study published in Science Advances.
The study, led by D. James Surmeier, PhD, the Nathan Smith Davis Professor and chair of Neuroscience, suggests the approach may alleviate increased involuntary movement triggered by long-term usage of the drug levodopa in patients with late-stage Parkinson’s disease.
“This symptomatic therapy is recreating a learning signal in the brain that, instead of being dictated by experience or by the need to move, is chemically induced. It’s driving aberrant learning, which leads to side effects with prolonged use at high doses. What we were trying to do is to block that aberrant learning and in so doing, eliminate the side effects of the treatment,” Surmeier said.
An estimated 8.5 million individuals currently live with Parkinson’s disease, according to the World Health Organization. Parkinson’s disease is characterized by the loss of dopaminergic neurons in specific locations in the midbrain that send signals to the brain to coordinate goal-directed movement and habit. The disease is progressive, and symptoms can include tremors, muscle stiffness and slow movement.
Although these symptoms can be managed effectively with medication in the early stages of the disease, as the disease progresses the efficacy of the medication wanes and side-effects commonly manifest.
Patients with late-stage Parkinson’s disease may also experience levodopa-induced dyskinesia (LID), or involuntary movement associated with taking the medication levodopa, a first-line therapy for treating the disease. Levodopa works by converting into dopamine in the brain, serving as a dopamine replacement. As Parksion’s disease progresses, the amount of levodopa needed to achieve symptomatic benefit rises and the ability of the brain to regulate its concentration falls, leading to long periods of time when brain concentration is very high or very low. This oscillation is thought to be responsible for LID.
“As the disease progresses, you’re losing more and more of the dopaminergic neurons that take up levodopa, convert it to dopamine and release it to modulate movement. When these neurons are lost, brain dopamine levels are not regulated properly and, paradoxically, you start having unwanted movements,” Surmeier said.
At this point, patients can either choose to reduce their levodopa dosage, which increases motor disability without a full restoration of function, or undergo deep-brain stimulation, in which electrodes are surgically implanted into the brain and deliver a mild electrical current to specific regions of the brain.
“Nobody ever wants to have brain surgery, so we’ve been trying to understand the mechanisms underlying dyskinesia to help us design better pharmacotherapies or gene therapies that don’t involve deep brain stimulation,” Surmeier said.
In the current study, Surmeier’s team used a combination of electrophysiological, pharmacological, molecular, and behavioral approaches to measure synaptic changes in striatal spiny projection neurons — the main population of neurons in the striatum that support movement control — in mice exhibiting symptoms of Parkinson’s disease that were treated with levodopa.
First, the scientists found that in the Parkinsonian mice, the striatal concentration of dopamine and acetylcholine alternated, mimicking signals that normally control learning and synaptic plasticity.
Next, they used genetic and pharmacological approaches to disrupt the acetylcholine receptors in spiny projection neurons necessary for learning. The scientists also tracked the mice’s movement and behavioral changes to determine how these two approaches impacted the severity of dyskinesia in the mice.
Using these two approaches, the scientists found that disrupting cholinergic signaling preserved synaptic connectivity in this subpopulation of neurons and improved the ability of levodopa to stimulate movement and blunted the severity of LID.
Therapeutically targeting this signaling using novel genetic approaches may alleviate LID while enhancing the symptomatic benefits of levodopa and reducing the need for invasive brain surgery, according to Surmeier.
“What our study suggests is that the symptomatic treatment of late-stage patients leads to aberrant learning in the striatum. What we found is that if we disrupt that aberrant learning, we increase the symptomatic benefit of levodopa and at the same time diminish the dyskinesia,” Surmeier said.
Co-authors include Qiaoling Cui, PhD, research assistant professor of Neuroscience; David Wokosin, PhD, research associate professor of Neuroscience; and Tatiana Tkatch, PhD, research professor of Neuroscience.
This work is supported by the JPB foundation, the National Institute of Neurological Disorders and Stroke grant R37-NS34696, the William N. and Bernice E. Bumpus Foundation, Aligning Science Across Parkinson’s (ASAP020551) through the Michael J. Fox Foundation for Parkinson’s Research, J. and J. Schattinger, and R. Buxton.
