UC Berkeley

Over the past few decades, neuroscientists have been finding a growing number of roles for microglia and astrocytes in brain development and homeostasis. Consequentially, both of these glial cells are also now identified to be implicated in almost all neurological disorders. This thesis discusses work on two separate projects that each discovers novel roles for microglia or astrocytes in a specific disease context. Chapter two discusses a project that explores the role of copper in microglial inflammation. We find that copper pools with microglial cell bodies increase when cells are presented with an inflammatory stimuli. Previous epidemiological data has identified copper as a risk factor for the development of neurodegenerative disorders, like Parkinson’s Disease (PD). Interestingly, increased neuroinflammation is also prominently associated with all neurodegenerative diseases. Therefore, we have now created a mouse system to test whether or not inflammation-induced PD-like symptoms are impacted by copper levels. Chapter three describes a project that discovers a role for transcription factor 4 (Tcf4) in astrocytes. We initially thought that Tcf4 could potentially be important for microglial inflammation, as we generated Tcf4 knock-down microglia cell lines that exhibited impaired inflammation. However, we then found that astrocytes highly express Tcf4 in mouse brain, while microglia levels are undetectable. Lastly, we generated a mouse model in which Tcf4 was specifically deleted in astrocytes. Intriguingly, these mice exhibited shortened life-spans, seizures, and anatomical brain abnormalities, none of which were observed in the control mice. Together, this work demonstrates that both microglia and astrocytes are involved in neurological diseases in ways that were not previously known. As the etiology and treatment of both PD and epilepsy are relatively unknown, we hope that this work can contribute to the development of new therapeutic options.