A new Northwestern Medicine study challenges traditional ideas about how dopamine influences movement, according to findings published in Science Advances.
The study, led by D. James Surmeier, PhD, the Nathan Smith Davis Professor and chair of Neuroscience, revealed an unexpected role for support cells called astrocytes and points to potential new therapeutic targets for Parkinson’s disease.
The study found that during movement, dopamine does far more than regulate signaling in the striatum, a region of the brain traditionally viewed as the primary site of the neurotransmitter’s influence on movement. Instead, the scientists discovered that dopamine also acts within another key movement-control center, the substantia nigra pars reticulata (SNr), where it works through astrocytes to shape neural activity.
“As is often the case, our experiments led to unexpected findings,” said Surmeier, who was the senior author of the study. “One of the most unexpected things that we saw was that when we engaged dopaminergic receptors, it led to an increase in the discharge rate of substantia nigra pars reticulata neurons.”
The findings emerged from experiments in mouse brain tissue slices examining how dopamine affects communication within the basal ganglia, a network of brain regions essential for movement control and heavily affected in Parkinson’s disease. The team of investigators initially set out to verify previous inferences about dopamine’s effects on inhibitory signaling. In the process, they uncovered a surprising phenomenon.
For decades, the conventional model has suggested that dopamine promotes movement largely by suppressing activity in the SNr. The new findings suggest the opposite can occur, Surmeier said.
Using optogenetic techniques along with electrophysiological recordings, the team found that dopamine suppressed a form of inhibition controlled by another neurotransmitter, GABA. The source of that GABA turned out to be a subset of dopamine-producing neurons, while astrocytes regulated how much of the signal lingered in the surrounding environment. Specifically, dopamine stimulated astrocytes to increase GABA uptake, reducing inhibition and allowing SNr neurons to fire more rapidly.
“The most unexpected finding was that mimicking dopamine release by the dendrites of substantia nigra pars compacta neurons accelerated the discharge rate of SNR neurons, suggesting that the classical model of how movement was coded was not quite right,” Surmeier said. “The other thing is that it’s very clear that astrocytes are playing a role in regulating the basal ganglia circuitry.”
The study also uncovered evidence that dopamine neurons may use GABA in an entirely unexpected way. Investigators found that the GABA released by these neurons appears linked to cellular metabolism. Under conditions where energy demands rise, the neurons may use GABA as an alternative fuel source rather than releasing it.
“We actually were able to show that GABA, which was synthesized inside the dopaminergic neurons … could be used as an alternative fuel source for mitochondrial power plants inside those cells,” Surmeier said. “The amount of GABA that was being dumped was really a reflection of the metabolic state of the dopaminergic neurons.”
Beyond providing new insight into basic brain function, the findings may have important implications for Parkinson’s disease. Parkinson’s symptoms arise when dopamine-producing neurons degenerate, but growing evidence suggests the disease cannot be explained solely by dopamine loss in the striatum. The new work adds to that body of research by highlighting the importance of dopamine signaling in the SNr.
“I think the biggest take-home and the most significant implications of the work have to do with the fact that our models of how the basal ganglia and dopamine in particular modulate movement are in need of major revision,” Surmeier said.
According to Surmeier, rethinking that model could open new treatment avenues. Current therapies and emerging gene therapies largely focus on restoring dopamine function in the striatum. However, the new findings suggest that targeting the substantia nigra pars reticulata could also provide therapeutic benefit and may offer practical advantages because the region is much smaller and potentially easier to manipulate.
“It also has therapeutic implications because it tells us that the striatum is not the only place that we can intervene and have a positive therapeutic impact,” Surmeier said.
While additional studies will be needed to translate the findings into treatments, the work provides a new framework for understanding how dopamine shapes movement and how those mechanisms break down in Parkinson’s disease.
“Sometimes, it’s the unexpected that turns out to be the most interesting and important thing in a study,” Surmeier said.
The study was supported by a fellowship from the Bumpus Foundation, as well as grants from the Freedom Together Foundation, the U.S. Department of Defense (W81XWh2110749), and Aligning Science Across Parkinson’s (ASAP020551) through the Michael J. Fox Foundation for Parkinson’s Research.
