Frontotemporal Dementia (FTD) is the most common form of presenile dementia and is characterized by impaired cognitive function, behavioral changes, or non-fluent speech aphasia. The most common genetic cause of FTD is a hexanucleotide GGGGCC (G4C2) repeat expansion in the C9orf72 gene (C9orf72-HRE). This thesis outlines a series of in vivo and in vitro experiments undertaken to investigate the molecular mechanisms of toxicity contributing to FTD pathogenesis. In my efforts to characterize the neuroinflammation observed in our Poly(Glycine-Arginine) mouse model of FTD, I found Fkbp5 - a gene our lab previously identified as a modulator of Poly(GR) toxicity - to be significantly downregulated in the cortex of Poly(GR) animals relative to controls. Published RNA sequencing data suggests that Fkbp5 is most highly expressed in microglia of the mammalian brain. However, despite its importance in a variety of neurological disorders, very little is known about the specific role fkbp5 plays in microglia. Data presented in this thesis implicate Fkbp5 as an important modulator of neuroinflammatory signaling and Poly(GR) toxicity. Here, I outline the breeding scheme I devised to generate a novel genetic tool to further untangle the role Fkbp5 may be playing in neuroinflammation and C9orf72 pathogenesis. In additional efforts to investigate the molecular underpinnings of C9orf72 pathology, I contributed to the characterization of a novel AAV9 model of C9orf72-HRE developed by our collaborators at SUNY Upstate Medical University.