Gordon Holmes syndrome (GHS) is a neurodegenerative disease that results in hypogonadotropic hypogonadism, cognitive impairment, ataxia, and neurodegeneration. Hypogonadotropic hypogonadism is characterized by an impaired hypothalamic-pituitary-gonadal (HPG) axis and consists of decreases in gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) release. Although the HPG axis is well studied, there is a gap in our knowledge of how mutations in E3 ubiquitin ligases lead to HPG axis dysfunction. Clinical familial cases have identified genetic mutations in the E3 ubiquitin ligase, RNF216/TRIAD3 which is involved in the removal or ubiquitination of proteins in the nervous system. E3 ubiquitin ligases play a crucial role in a diversity of biological processes; therefore, understanding their function in the HPG axis function, learning, and degeneration is critical for identifying therapeutic intervention strategies to limit neurological disease burden. The overall objective of this dissertation was to determine how deletion of Rnf216/Triad3 alters multiple levels of the HPG axis, cognitive and motor behaviors, and neuroinflammation. To address the functions of RNF216/TRIAD3 in vivo, we generated a Rnf216/Triad3 knockout (KO) mouse. We found that this model demonstrated profound differential HPG axis phenotypes in both sexes. We also found that while neither the male nor female KO mice displayed prominent motor phenotypes, only KO females displayed an abnormal clasping phenotype. In memory behavior, there were age-specific and sex-specific impairments in both spatial learning and associative learning. Correlated with these behavioral phenotypes, there was a male-specific reduction of reactive microglial area in the hippocampus, cortex, and hippocampus while this is not seen in female KO mice. Conditional deletion of Rnf216/Triad3 in neural and glial stem cells in male mice did not recapitulate reproductive, motor, or memory behavior. However, we found that removal of Rnf216/Triad3 in neural stem precursor cells led to altered microglial expression. Our findings show that RNF216/TRIAD3 modulates reproductive, learning, and neuroinflammation.