Early Detection of Male-Predominant Phenotypes in the Pattern of Ultrasonic Vocalizations Emitted by Autism Spectrum Disorder Model (Crmp4-Knockout) Mice

Male predominance is a known feature of autism spectrum disorder (ASD). Although ASD mouse models can be useful for elucidating mechanisms underlying abnormal behaviors relevant to human ASD, suitable models to analyze sex differences in ASD pathogenesis remain insufficient. Herein, we used collapsin response mediator protein 4 (Crmp4)-knockout (KO) mice exhibiting ASD-like phenotypes in a male-predominant manner and analyzed ultrasonic vocalizations (USVs) to detect potential differences between genotypes and sexes during the early postnatal period. We recorded isolation-induced USVs emitted from wild-type (WT) and Crmp4-KO littermates and compared the total number of USVs between genotypes and sexes. We classified USVs into 10 types based on internal pitch changes, lengths, and shapes and compared the number of USVs in each type by genotypes and sex. Male Crmp4-KO mice exhibited a reduction in the total number of USVs. Crmp4-KO decreased the number of USVs in 7 out of 10 USV types, and male KO mice exhibited a greater reduction than females in 3 of the 7 types. This study offers a suitable ASD animal model and tool for assessing sex-based communication deficits during the early postnatal period, both of which would be valuable for elucidating the underlying mechanism.