Dynamics of and Function Cerebellar Microglia

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Abstract: Synaptic plasticity allows the central nervous system (CNS) to incorporate new sensory experiences and information, and its disruption is associated with many neurological and psychiatric disorders. Much recent work has focused on the contribution of non-neuronal CNS cells, especially microglia, the innate immune cells of the CNS, to synaptic plasticity. Though classically thought of in their immune capacities, microglia are vital to many homeostatic and developmental processes, including synaptic plasticity of nascent and adult neuronal networks. Despite the emerging consensus that microglial dynamics are critical to brain function during physiological as well as pathological conditions, it is unclear whether these microglial roles and their underlying mechanisms are universal or differ between brain regions. There is a growing body evidence to suggest microglia exhibit a high degree of regional specialization; existing on a continuum from homeostatic (cortex, striatum) to immune vigilant (cerebellum) even in the absence of pathological stimuli. Indeed, microglia in the cerebellum represent a distinct population, exhibiting unique transcriptional and epigenetic profiles, along with distinct functional properties, such as being more phagocytic, morphologically less ramified and less densely distributed. As a consequence, cerebellar microglia survey less of the brain parenchyma than cortical microglia, but compensate for this by undergoing frequent somatic translocations under homeostatic conditions, a phenomenon not observed in cortex. Despite these differences, cerebellar microglia maintain common microglial functions, exhibiting a robust injury response and dynamic interactions with surrounding neural elements. Understanding the common and unique roles of cerebellar microglia, along with the mechanisms that mediate such roles, will be critical to understanding both cerebellar function and plasticity, as well as the heterogeneity of microglia throughout the brain. In this proposal, I will address the hypothesis that cerebellar microglia use a subset of the conserved mechanisms that modulate microglial dynamics to directly interact with the cerebellar microcircuit to modulate cerebellar neuronal plasticity. To test this hypothesis I have developed the following specific aims: In Aim 1 I will investigate how two important mechanisms that are known to be key to microglial mediated neural plasticity in the cortex shape the dynamics and injury response of cerebellar microglia. In Aim 2 I will investigate the importance of one of these mechanisms, b2 adrenergic receptor signaling, with known roles in cerebellar plasticity, to microglial modulation of cerebellar circuits and behavior. The results obtained from these complementary but independent aims will further our understanding of cerebellar microglia, illuminating both the signaling pathways that govern their dynamics and their contribution to cerebellar neuronal plasticity. From there, we can begin to unravel how different microglial populations serve their roles in the brain and gain insight into how defects in microglia- mediated synaptic plasticity contribute to neurological and psychiatric diseases.