Age‐specific autistic‐like behaviors in heterozygous Fmr1‐KO female mice

Abstract

Fragile X syndrome (FXS) is a major developmental disorder and the most frequent monogenic cause of autism. Surprisingly, most existing studies on the Fmr1-KO mouse model for FXS have focused on males, although FX women, who are mostly heterozygous for the Fmr1 mutation, are known to exhibit several behavioral deficits, including autistic-like features. Furthermore, most animal research has been carried out on adults only; so that little is known about the age progression of the behavioral phenotype of Fmr1 mutants, which is a crucial issue to optimize the impact of therapeutic interventions. Here, we performed an extensive analysis of autistic-like social behaviors in heterozygous (HET) Fmr1-KO females and their WT littermates at different ages. No behavioral difference between HET and WT mice was observed at infancy, but some abnormalities in social interaction and communication were first detected at juvenile age. At adulthood some of these alterations disappeared, but avoidance of social novelty appeared, together with other FXS-relevant behavioral deficits, such as hyperactivity and reduced contextual fear response. Our data provide for the first time evidence for the presence of autistic-relevant behavioral abnormalities in Fmr1-HET female mice, demonstrating the utility of this mouse line to model autistic-like behaviors in both sexes. These results also highlight the importance of taking into account age differences when using the Fmr1-KO mouse model, suggesting that the early post-natal phases are the most promising target for preventive interventions and the adult age is the most appropriate to investigate the behavioral impact of potential therapies. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1067-1078. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

High‐throughput analysis of vocalizations reveals sex‐specific changes in Fmr1 mutant pups

“…10 In the present study, comprehensive analysis detected a significant increase in the average duration of these calls in male KO pups only. A previous study conducted in the C57/BL6J strain using the same recording setup on PD8 did not find any changes between female Fmr1 HETs and WTs in number and mean duration of USVs, peak amplitude, peak frequency and duration of calls between subsequent calls.…”

“…10 It should be noted that significant differences exist between the Fmr1 KO phenotypes on the different background strains commercially available, like many transgenic models. 10 It should be noted that significant differences exist between the Fmr1 KO phenotypes on the different background strains commercially available, like many transgenic models.…”

Deletion of Fmr1 results in sex‐specific changes in behavior

“…Given that most of these behavioral paradigms only span one day, it is possible that differences could reflect differences in estrous cycles between groups. A recent study comparing heterozygous Fmr1 mutants did assess the estrous cycle of subjects, however, it was shown that estrous cycle did not significantly impact the results shown (Gauducheau et al., 2017). Furthermore, a recent meta‐analysis of 293 articles found that variability was not greater in females for behavioral tasks when they did not account for the estrous cycle (Prendergast et al., 2014).…”

“…This typically leads to behavioral variability, which can be typically attributed to a gene dosage effect. Previous studies have examined behavior in the heterozygous Fmr1 female, but few differences were noted between homozygous and heterozygous females, mostly limited to juvenile aged animals (Gauducheau et al., 2017; Qin et al., 2005). Although previous studies have suggested that potential differences in female Fmr1 KOs, as well as human clinical data, are linked directly to a gene dosage effect, the behavioral differences noted in this study are independent of Fmr1 expression.…”

“…Recent experimental evidence has also shown that female Fmr1 KOs present normal fear learning and anxiety, but show impaired fear memory (Nguy & Tejada-Simon, 2016). Furthermore, analysis of behaviors at different ages has shown sex-specific differences in ultrasonic vocalization production (Reynolds, Nolan, Jefferson, & Lugo, 2016), though other strains have not shown this effect (Gauducheau et al, 2017). In a recently published review, authors summarized the effects of Fmr1 deletion across both male and female mice, noting that some behaviors have sex-specific effects, though most behaviors have not yet been examined in females (Romano, Cosentino, Laviola, & De Filippis, 2016).…”