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Gordon Holmes syndrome (GHS) is a neurological disorder associated with neuroendocrine, cognitive, and motor impairments with corresponding neurodegeneration. Mutations in the E3 ubiquitin ligaseRNF216are strongly linked to GHS. Previous studies show that deletion ofRnf216in mice led to sex-specific neuroendocrine dysfunction due to disruptions in the hypothalamic–pituitary–gonadal axis. To address RNF216 action in cognitive and motor functions, we testedRnf216knock-out (KO) mice in a battery of motor and learning tasks for a duration of 1 year. Although male and female KO mice did not demonstrate prominent motor phenotypes, KO females displayed abnormal limb clasping. KO mice also showed age-dependent strategy and associative learning impairments with sex-dependent alterations of microglia in the hippocampus and cortex. Additionally, KO males but not females had more negative resting membrane potentials in the CA1 hippocampus without any changes in miniature excitatory postsynaptic current (mEPSC) frequencies or amplitudes. Our findings show that constitutive deletion ofRnf216alters microglia and neuronal excitability, which may provide insights into the etiology of sex-specific impairments in GHS.