Cerebellar microglia: On the edge between neuroinflammation and neuroregulation

The cerebellum is receiving increasing attention for its cognitive, emotional, and social functions, as well as its unique metabolic profiles. Cerebellar microglia exhibit specialized and highly immunogenic phenotypes under both physiological and pathological conditions. These immune cells communicate with intrinsic and systemic factors and contribute to the structural and functional compartmentalization of the cerebellum. In this review, we discuss the roles of microglia in the cerebellar microenvironment, neuroinflammation, cerebellar adaptation, and neuronal activity, the associated molecular and cellular mechanisms, and potential therapeutic strategies targeting cerebellar microglia in the context of neuroinflammation. Future directions and unresolved questions in this field are further highlighted, particularly regarding therapeutic interventions targeting cerebellar microglia, functional mechanisms and activities of microglia in the cerebellar circuitry, neuronal connectivity, and neurofunctional outcomes of their activity. Cerebellar morphology and neuronal performance are influenced by both intrinsic and systemic factors that are actively monitored by microglia in both healthy and diseased states. Under pathological conditions, local subsets of microglia exhibit diverse responses to the altered microenvironment that contribute to the structural and functional compartmentalization of the cerebellum. Microglia in the cerebellum undergo early maturation during the embryonic stage and display specialized, highly immunogenic phenotypes. In summary, cerebellar microglia have the capacity to serve as regulatory tools that influence outcomes across a wide range of neurological and systemic conditions, including neurodevelopmental, neurodegenerative, metabolic, and stress-related disorders.