Exploring the Dynamics of Social Interactions During the Juvenile Stage in a Mouse Model of Fragile X Syndrome

IntroductionFragile X Syndrome (FXS), caused by Fmr1 mutations, is linked to cognitive and behavioral differences, including altered social interactions. Most mouse studies focus on adults, despite human research showing critical developmental changes in childhood and adolescence. We examined social behavior in juvenile male and female Fmr1 knockout (KO) mice as well as heterozygous (HET) females. We further assessed cortical activity in KO females to better understand early phenotypes. MethodsJuvenile mice of both sexes and genotypes were paired in same-sex, novel dyads for 10-minute interactions. Key social behaviors such as head, anogenital, and body sniffing, and physical touch, as well as distance travelled, were analyzed with a marker-less tracking software. Frontal-parietal EEG recordings were collected from wild-type (WT) and KO females in home cage and social contexts to analyze power spectra across frequency bands. ResultsHET and KO females engaged in more frequent but shorter interaction events compared to WT females, with HET females showing the highest counts. Males displayed similar trends when comparing KO and WT. Males engaged in overall higher interaction events than females. EEG analyses revealed altered oscillatory activity in KO females compared to WT females, especially within theta, alpha, and beta bands, most prominently during the early interaction phase. Locomotor activity correlated weakly with head/anogenital sniffing but more strongly with body sniffing and touch. DiscussionThese findings suggest that Fmr1-related differences in juvenile social behavior are sex-dependent and associated with cortical oscillatory changes. Characterizing these early phenotypes in both sexes allows us to further understand FXS development and informs potential routes for early intervention. Key PointsO_LIFragile X Syndrome (FXS), the leading inherited cause of autism, is associated with disruptions in social behavior. C_LIO_LIWhile social phenotypes are relatively well described in adult mouse models of FXS, juvenile manifestations remain poorly understood. C_LIO_LISocial behavior was assessed in juvenile male and female Fmr1 knockout (KO), heterozygous (HET, female only), and wildtype (WT) mice, and frontal-parietal EEG recordings were collected from WT and KO females. C_LIO_LIHET and KO females exhibited more frequent but shorter social interactions than WT females, with HET showing the greatest number of events. Males showed similar patterns when comparing KO and WT. Males engaged in higher overall interaction events than females. EEG recordings revealed altered oscillatory activity in KO compared to WT females, most pronounced during the early phase of social encounter. C_LIO_LIThese findings reveal sex- and genotype-dependent differences in juvenile social behavior and cortical activity, highlighting the importance of studying juvenile development in FXS. C_LI