Date of Award
Doctor of Philosophy (PhD)
David Feliciano, PhD
William Baldwin, PhD
Yanzhang Wei, PhD
Emily Rosowski, PhD
Microglia are the primary immune cells of the central nervous system and contribute substantially to both development and maintenance of the brain. Negative alterations to microglia often result in detrimental outcomes and significant effort is being made to understand these powerful cells. The goal of this research is to characterize microglia in the developing and diseased murine dorsal telencephalon. In vivo cell labeling and confocal microscopy identified a transient cell type, amoeboid microglia cells (AMCs), that appear to contribute to the development of microglia. Moreover, the spatial distribution and morphological change of microglia was thoroughly characterized during postnatal development. The role of extracellular vesicles (EVs) in the postnatal development of microglia was also explored. EVs are membranous particles utilized for drug delivery and diagnostics and offer an exciting new therapeutic approach. A Transgenic Inducible GFP EV Reporter (TIGER) mouse was used to identify sources of EVs in the developing brain. Neonatal astrocytes were identified as a source of EVs using TIGER mice. These findings were also confirmed in vitro. In vivo studies using a Rab27a shRNA demonstrated the contribution of astrocyte EVs to the spatial distribution of microglia during development. The crosstalk between astrocytes and microglia via EVs was then examined in a mouse model of tuberous sclerosis complex (TSC). Loss of Tsc2 in neural progenitor cells and progeny, including astrocytes, resulted in a decrease in microglia cell density. Moreover, microglia significantly decreased the release of cytokines in response to Tsc2 mutant astrocytes EVs. Studies in the Tsc2 mutant mouse suggest that astrocytes may partly contribute to the immunological landscape in the TSC brain. The ability of diseased astrocytes to modulate microglia via EVs, suggests that EVs should be further examined for therapeutic and diagnostic potential.
Neckles, Victoria, "The Characterization of Microglia in the Murine Dorsal Telencephalon in Development and Disease" (2022). All Dissertations. 3225.
Available for download on Sunday, December 31, 2023