Mutations associated with autism lead to similar synaptic and behavioral alterations in both sexes of male and female mouse brain

Abstract

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder based on synaptic abnormalities. The estimated prevalence rate of male individuals diagnosed with ASD prevails over females is in a proportion of 4:1. Consequently, males remain the main focus in ASD studies in clinical and experimental settings. Meanwhile, some studies point to an underestimation of this disorder in females. In this work, we studied the sex differences of the synaptic and behavioral phenotypes of ASD mouse models. Juvenile male and female Shank3Δ4–22 and Cntnap2−/− mutant mice and their WT littermates were used in the experiments. The animals were subjected to a Three-Chamber Sociability Test, then euthanized, and the whole cortex was used for the evaluation of the synaptic phenotype. Protein levels of glutamatergic (NR1) and GABAergic (GAD1 and VGAT) neuronal markers were measured. Protein level of synaptophysin (Syp) was also measured. Dendritic spine density in somatosensory neurons was analyzed by Golgi staining methods. Spine Density and GAD1, NR1, VGAT, and Syp levels were significantly reduced in Shank3Δ4–22 and Cntnap2−/− mice compared to the control group irrespective of sex, indicating impaired synaptic development in the mutant mice. These results were consistent with the lack of differences in the three-chamber sociability test between male and female mice. In conclusion, female ASD mice of both mutations undergo similar synaptic aberrations as their male counterparts and need to be studied along with the male animals. Finally, this work urges the psychiatry scientific community to use both sexes in their investigations.