Activity of the signaling molecule dopamine in the cerebellum plays a key role in regulating social behavior, a new study in mice reveals.
The cerebellum, a brain structure at the base of the skull, is traditionally thought to control movement. But mounting evidence suggests it also plays a role in social behavior and other complex cognitive functions — a link that has led to a growing interest in structure among autism researchers.
Dopamine signaling in other brain regions is also known to be involved in social behavior, but few studies have looked at dopamine in the cerebellum. The new study links the social role of dopamine in the cerebellum to a specific cell type in a specific region, similar to the way functions such as language and visual processing reside in certain areas of the cerebral cortex.
The task of matching location and function in the cerebellum was particularly difficult, making the work “groundbreaking,” said Sam Wang, a professor of neuroscience at Princeton University, who was not involved in the study. “It offers some solution to the question of how the cerebellum might be involved in regulating higher functions.”
lIn the past, scientists had trouble mapping the location of dopamine receptors in the cerebellum — proteins that sit on the cell surface and bind to the molecule. Not only are there relatively few of them, but experimental techniques weren’t sensitive enough to pinpoint their location, said study leader Emmanuel Valjent, director of research at the National Institute of Health and Medical Research (INSERM) and the Institute of Functional Genomics at the University. from Montpellier in France.
Valjent and his collaborators used two genetically engineered mouse lines to show that a particular class of dopamine receptors, known as D2 receptors, is found in the outer layer of the cerebellum. In particular, the D2 receptors are mainly found on Purkinje cells, which integrate and filter information and then relay signals from the cerebellum to other parts of the brain. Postmortem brains of people with autism show a loss of Purkinje cells.
“The dopamine is there, and the function may be more important than we expect,” Valjent says.
Chemically stimulating the D2 receptor in slices of the cerebellum of mice suppressed excitatory signaling, indicating one way Purkinje cells do their job of modulating and integrating neuronal signaling, Valjent says. The work appeared on June 16 in Nature Neuroscience†
To gain more insight into the function of dopamine signaling in the cerebellum, the researchers next used a genetically engineered virus to turn off D2 receptor activity in Purkinje cells in adult male mice.
Because of the known role of the cerebellum in coordinating movement, “we expected to find a motor impairment by manipulating the level of the D2 receptor,” Valjent says. “But there was nothing.” The mice without D2 receptor activity in Purkinje cells ran around, balanced on a bar and rode on a rotating bar just as well as control mice.
TThe researchers were at an impasse when one of the first papers on cerebellar dopamine emerged in 2019, implicating dopamine in the deep cerebellar nuclei in social behavior. Inspired by those results, Valjent and his colleagues decided to test social behavior in the animals. Mice lacking D2 receptor activity in Purkinje cells spent more time sniffing another mouse in their cage than control mice, and also showed a stronger preference for a newly introduced mouse over a familiar one.
A second genetically engineered virus designed to enhance expression of the D2 receptor in Purkinje cells resulted in mice with the opposite characteristics: They were less interested in interacting with other mice and less interested in mice they hadn’t before. met compared to controls.
D2 receptors are most abundant on Purkinje cells in Crus I and Crus II, regions of the cerebellum previously involved in social behavior. When the researchers manipulated D2 receptor levels in Purkinje cells only in Crus I and Crus II, it had the same effects on social behavior as changing D2 levels in the cerebellum as a whole.
“They were able to show that the Purkinje cell expression of the D2 dopamine receptor was not only necessary and sufficient in the whole cerebellum to change this behavior, but really in that targeted area,” said Erik Carlson, assistant professor psychiatry and behavioral sciences at the University of Washington in Seattle. “That’s really surprising; that’s really deep and really powerful.”
However, because D2 receptors are also found elsewhere in the cerebellum and in cell types other than Purkinje cells, “they have not ruled out the possibility that there are other cells involved in this function of dopamine,” Wang says.
Valjent and his team are now investigating cerebellar D2 receptors in the brains of several mouse models of autism, including mice lacking the genes FMR1, MECP2, and SHANK3.
Cite this article: https://doi.org/10.53053/PAKY1634