:Multiple sclerosis is an autoimmune disorder of the central nervous system (CNS) characterized by locomotor impairments, cognitive deficits, affective disorders, and chronic pain. Females are predominately affected by MS compared to males and develop motor symptoms earlier. However, key symptoms affect all patients regardless of sex. Previous studies have shown that demyelination and axonal damage play key roles in symptom development, but it is unclear why sex differences exist in MS onset, and effective symptom treatment is still lacking. We here used a non-pertussis toxin (nPTX) experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice, to explore chronic symptoms and sex differences in CNS autoimmunity. We observed that, like in humans, female mice developed motor disease earlier than males. Further, changes in pre- and post-synaptic protein expression levels were observed in a sexually dimorphic manner with an overall shift towards excitatory signaling. Our data suggest that this shift towards excitatory signaling is achieved through different mechanisms in males and females. Altogether, our study helps to better understand sex-specific disease mechanisms to ultimately develop better diagnostic and treatment tools.