Courtesy of Emmanuel Valjent 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 located at the base of the skull, is traditionally thought to control movement. But growing evidence suggests it also plays a role in social behavior and other complex cognitive functions—a connection that has sparked growing interest in the structure among autism researchers. Dopamine signaling in other brain regions is also known to be involved in social behavior, but few studies have examined dopamine in the cerebellum. The new study links the social role of dopamine in the cerebellum to a specific type of cell in a specific region, similar to how functions such as language and visual processing are localized to specific parts of the cerebral cortex. The task of mapping location and function in the cerebellum has been particularly difficult, which makes the work “groundbreaking,” says Sam Wang, a professor of neuroscience at Princeton University who was not involved in the study. “It provides some resolution to the question of how the cerebellum could possibly be involved in the regulation of higher functions.” In the past, scientists have had trouble mapping the location of dopamine receptors—proteins found on the cell surface that bind to the molecule—in the cerebellum. Not only are there relatively few of them, but experimental techniques were not sensitive enough to pinpoint their locations, says study leader Emmanuel Valjent, director of research at the National Institute for Health and Medical Research (INSERM) and the Institute of Functional Genomics at the University of Montpellier in France. Valjent and colleagues used two lines of genetically engineered mice to show that a specific class of dopamine receptors, known as D2 receptors, are found throughout the outer layer of the cerebellum. Specifically, D2 receptors are found primarily on Purkinje cells, which integrate and filter information and then pass signals from the cerebellum to other parts of the brain. Postmortem brains of individuals with autism show loss of Purkinje cells. “The dopamine is there, and the function is probably more important than we expect,” says Valjent. Chemical stimulation of the D2 receptor in mouse cerebellar slices reduced excitatory signaling, indicating one way Purkinje cells do their job of regulating and integrating neuronal signaling, Valjent says. The project appeared on June 16 Nature Neuroscience. To gain more insight into the function of dopamine signaling in the cerebellum, the researchers then used a genetically engineered virus to disable D2 receptor activity in Purkinje cells in adult male mice. Because of the cerebellum’s known role in coordinating movement, “we expected to find a motor impairment by manipulating the level of the D2 receptor,” says Valjent. “But there was nothing there.” Mice lacking D2 receptor activity in Purkinje cells ran, balanced on a beam, and rode a spinning rod just as well as control mice. Researchers hit a snag when, in 2019, one of the first papers on dopamine in the cerebellum appeared, implicating dopamine in the deep cerebellar nuclei in social behavior. Inspired by these results, Valjent and his colleagues decided to test social behavior in animals. Mice lacking D2 receptor activity in Purkinje cells spent more time smelling another mouse placed in their cage than control mice, and also showed a greater preference for a newly introduced mouse over a familiar one. A second genetically engineered virus designed to enhance the 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 had not encountered before compared to controls. D2 receptors are most abundant in Purkinje cells in Crus I and Crus II, regions of the cerebellum previously implicated in social behavior. When the researchers manipulated D2 receptor levels in Purkinje cells in Crus I and Crus II alone, they produced the same effects on social behavior as changing D2 levels in the cerebellum as a whole. “They were able to show that Purkinje cell expression of the D2 dopamine receptor was not just necessary and sufficient throughout the cerebellum to change these behaviors, but really in this focused region,” says Erik Carlson, assistant professor of psychiatry and behavioral sciences. scientist. at the University of Washington in Seattle. “This is really amazing. that’s really deep and really powerful.” Because D2 receptors are also found elsewhere in the cerebellum and in cell types other than Purkinje cells, however, “they have not ruled out the possibility that there are other cells involved in this function of dopamine,” says Wang. Valjent and his team are now investigating cerebellar D2 receptors in the brains of several mouse models of autism, including mice lacking the FMR1, MECP2 and SHANK3 genes. Cite this article:
