Dimethyl fumarate ameliorates behavioural and brain oscillatory alterations induced by prenatal valproic acid exposure in female rats.

Sex differences in the prevalence, age of onset of symptoms, and symptom presentation have been widely described in autism spectrum disorders, yet the mechanisms underlying these sex differences remain poorly characterized. Exposing rats prenatally to valproic acid (VPA) is widely used as a model to study autism-like phenotypes. Using this model, sex-specific neuroanatomical and functional characteristics were examined in adolescent rats. We found sex differences in cortical pyramidal neuron complexity, spine density, and morphology in VPA-prenatally exposed animals. The expression of autism has been linked to various processes such as inflammation, cell signalling, endothelial function, and myelination. Sex-specific analysis of cortical gene expression showed that male VPA-prenatally exposed rats had elevated expression of genes related to neuropeptide signaling (Pdyn, Adora2a, Drd2), whereas female VPA-prenatally exposed rats had lower expression of genes related to vascular permeability (Angptl4, Cldn5) and inflammation (Cyr61, Usp18). Dimethyl fumarate, an activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and clinically approved to treat multiple sclerosis, alleviated VPA-induced behavioural alterations in object recognition, anxiety-like behaviour, and social behaviour in female VPA-exposed rats. In addition, dimethyl fumarate corrected the associated VPA-induced changes in neuronal oscillatory power and cross-frequency coupling and suppressed microglial activity, with the latter occurring selectively in female animals. Together, these findings indicate sex as an essential consideration in the development of novel pharmacotherapies for autism. Dimethyl fumarate had therapeutic properties in VPA-prenatally exposed female rats, however further studies examining its therapeutic efficacy in other models of autism are required.