Brown, Jennifer2023-02-162023-02-162022-12https://hdl.handle.net/11299/252556University of Minnesota Ph.D. dissertation. December 2022. Major: Neuroscience. Advisors: Sylvain Lesne, Harry Orr. 1 computer file (PDF); ix, 213 pages.Neurodegenerative diseases such as Alzheimer’s and Parkinson’s impact large portions of the population. Though such diseases have distinguishing features, they also often share pathology and symptomology. Alpha synuclein (αSyn; gene SNCA) is a protein commonly found in a range of neurodegenerative conditions. αSyn can interact with tau and amyloid-beta to modulate disease phenotypes, but its normal functions remain incompletely characterized. To explore the contribution of αSyn to Alzheimer’s disease, I first asked whether reducing αSyn in a mouse model of Alzheimer’s would improve cognition. Using a translationally relevant strategy, the reduction of αSyn reveled a sex-specific effect whereby male, but not female, mice showed improved spatial memory. Follow-up studies with constitutive SNCA knockout mice revealed a previously unreported female-specific deficit in spatial learning and memory. Next, we utilized electrophysiology, immunofluorescence imaging and transcriptomics to elucidate potential mechanisms underlying this effect. Results revealed a novel impairment in long-term potentiation, as well as differential expression of genes related to learning and immune function in female mice in response to SNCA ablation. These results not only describe a novel sex-specific function of αSyn, but provide translationally-relevant information regarding the potential effects of using αSyn reduction as a therapeutic strategy for neurodegenerative conditions.enalpha synucleinbehaviorcognitiongene expressionneurodegenerationsex differencesThesis or Dissertation