Ferro, Austin2023-02-032023-02-032020-11https://hdl.handle.net/11299/252342University of Minnesota Ph.D. dissertation. 2020. Major: Neuroscience. Advisors: Marija Cvetanovic, Alfonso Araque. 1 computer file (PDF); vii, 103 pages.Spinocerebellar ataxia type 1 (SCA1) is a fatal dominantly inherited neurodegenerative disease. Even though there has been illuminating work on the effect of the disease-causing protein, a polyQ expanded ATAXIN-1 (ATXN1) on neurons, the relative contribution to disease of glia has been unknown. Here I present my work on glial-neuron interactions in the context of SCA1; focusing on the neuroinflammatory and activation of microglia as well as the previously undiscovered cell-autonomous effect of polyQ expanded ATXN1 on astrocytes. Using the Lysm-Cre Ikkβflx/tlx line to assess the role of microglial activation in the transgenic ATXN1[82Q] mouse model of SCA1, I show that inhibition of microglial reactivity does not have a large effect on SCA1 disease pathology. Instead, we found that the Lysm-Cre Ikkβflx/tlx line itself had motor performance deficits in the absence of Purkinje cell degeneration. Correlating with this motor performance deficiency, Lysm-Cre Ikkβflx/tlx mice had a prominent deficiency in climbing fiber removal onto Purkinje cells. Due to the low impact of microglia on SCA1 pathology, I then focus on astrocytes and in particular, astrocytic Kir4.1/Kcnj10. Astrocytic Kcnj10 was downregulated throughout the brain of the knock-in Atxn1154Q/2Q mouse line. To investigate the potential role of cell-autonomous effects of Atxn1 on astrocytic transcription, I used the novel conditional humanized ATXN1floxed 146Q/2Q line to delete polyQ expanded ATXN1 from astrocytes. Conditional astrocytic deletion of polyQ ATXN1 did not influence failure to gain weight nor a prominent effect on rotarod pathology. Yet, there was a trending rescue of Kcnj10 expression in the medulla, suggesting a cell-autonomous effect of ATXN1 on astrocytic transcription. In conclusion, my thesis work concerning the role of both microglia and astrocyte in the pathogenesis of SCA1 has revealed the importance of NFᴋB signaling in cerebellar development as well as the potential cell-autonomous effect of polyQ ATXN1 on astrocytes.enAstrocyteATAXIN-1GliaMicrogliaSCA1Thesis or Dissertation