Abstract Summary/Description
Gordon Holmes Syndrome (GHS) is a neurodegenerative disorder associated with mutations in the E3 ubiquitin ligase RNF216, leading to a range of neuroendocrine, cognitive, and motor impairments. Disruptions in the hypothalamic-pituitary-gonadal axis have been identified in Rnf216 knockout (KO) mice, suggesting a role for RNF216 in neuroendocrine function. To determine if RNF216 regulates cognitive and motor functions, we performed motor and learning tasks in adult and middle-aged male and female Rnf216 KO and Wildtype (WT) mice. Although no significant motor phenotypes were observed, female KO mice exhibited abnormal limb clasping. Both sexes displayed age-dependent deficits in strategy and associative learning. We next examined microglia density, area, soma size, and morphology in multiple brain regions of Rnf216 KO mice. Our results revealed sex- and region-specific changes: female KO mice exhibited increased microglia density in the hippocampus and smaller soma size, while male KO mice had reduced microglia intersections in the cortex. We also observed unexpected changes in lateral ventricular size in Rnf216 KO mice. Our findings reveal neurobehavioral, structural, and microglial alterations in Rnf216 KO mice. Future experiments will use conditional knockout strategies to determine if selective deletion of Rnf216 in microglia causes similar phenotypes to Rnf216 global KO mice.
