Decoding sex-specific vocal repertoire and syntactic usage in the Fragile X mouse model of autism

Abstract Pup-dam ultrasonic vocalizations (USVs) contribute to the formation of neural circuits and behaviors essential for standard cognitive and socio-emotional development. In conditions like autism and Fragile X Syndrome (FXS), disruptions in pup-dam USV communication hint at a possible connection between abnormal early developmental USV communication and the later emergence of communication and social deficits. Syntax, a crucial element of rodent "language," has rarely been investigated in FXS mice, let alone in specimens of both sexes. Therefore, in this study, we gathered USVs from PND 10 FXS pups during a short period of separation from their mothers, encompassing animals of all possible genotypes and both sexes (i.e., Fmr1-/y vs. Fmr1+/y males and Fmr1+/+ , +/- , and -/- females). This allowed us to compare, for the first time, the relative influence of sex and gene dosage on their communication capabilities. Leveraging DeepSqueak and analyzing vocal patterns, we examined intricate vocal behaviors such as call structure, duration, frequency modulation, and temporal patterns. The results demonstrate that FMRP-deficient pups of both sexes display an increased inclination to vocalize when separated from their mothers, and this behavior is accompanied by significant sex-specific changes in the main features of their USVs as well as in body weight. Moreover, the decoding of the vocal repertoire and its syntactic usage revealed that the silencing of the Fmr1 gene primarily alters the qualitative composition of ultrasonic communication in males. These findings highlight the fascinating interplay between Fmr1 gene dosage and sex in shaping communication during infancy.