| Abstract/Results: | ABSTRACT:
Despite great advances in neuroscience research, knowledge on the mechanisms behind the origin of neuropsychiatric disorders, as well as possible therapies, are still lacking. Recently, the neuroimmune system has been studied in the context of these diseases, with emphasis given to microglia, due to their role in brain development. Microglia are known to regulate the pool of neuronal precursors and aid in neuronal circuit formation, as well as having a role in brain homeostasis in adulthood. Microglia constantly scan the brain for potential threats, undergoing immune activation in response to varied stimuli, then triggering inflammatory processes. In the context of neuropsychiatric diseases, activated microglia have been found in the brain of patients. Moreover, microglia dysfunction in critical periods of brain maturation has been hypothesized to contribute to circuitry alterations underlying these disorders.Microglia are heterogenous throughout different brain regions. Due to particularities of microglia in the cerebellum, including an enhanced clearance phenotype and activation priming, and the involvement of this brain region in regulating motor and social behaviors, the main goal of this thesis was to understand if challenging microglia function in critical periods of cerebellar maturation contributes to circuitry and behavioral alterations. In this work, it was showed that the maturation of cerebellar microglia is heavily hindered by IL-4, a Th2 anti-inflammatory cytokine considered as neuroprotective in neurodegeneration. IL-4 injection in mice not only affected microglia morphology, density and distribution in the cerebellum, but also induced alterations in Purkinje cell connectivity, ultimately leading to long-lasting behavioral abnormalities, such as motor coordination deficits, enhanced mobility and altered sociability. This work highlights the vulnerability of cerebellar maturation to environmental stimuli during the second postnatal week.
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