Sex-specific and genotype-specific differences in vocalization development in FMR1 knockout mice

Abstract

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide (CGG) hyperexpansion in the FMR1 gene, functionally silencing transcription of the fragile x mental retardation protein (FMRP). This disorder is characterized by impaired cognition, communication, and social behavior. The purpose of this study was to investigate the development of ultrasonic vocalization (USV) behavior in a FMR1 deficient mouse model. On postnatal days (PD) 9–14, separate cohorts of FVB/NJ pups were removed from their home cage and isolation-induced USVs were recorded. There were significant genotype- and sex-dependent differences in USV behavior across the different testing days. FMR1 knockout mice showed a significant reduction in vocalizations across all days. There was also a significant difference in vocalizations between male and female mice. We found a significant decrease in total number of calls for KO males on PD9 and PD13, as well as an increase in the total number of calls for KO males on PD12. The KO males also had a significant increase in total call duration on PD12 and a reduction on PD13. The KO female had a significant decrease in the total number of calls on PD9 and PD10. They also had a significant decrease in the total call duration on PD9 and a marginal decrease in total call duration on PD10. These results provide additional evidence for communication deficits in FMR1 deficient mice and provide new insight suggesting sexually dimorphic vocalizations during the neonatal period.

Deletion of Fmr1 results in sex‐specific changes in behavior

“…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).…”

NS‐Pten knockout mice show sex‐ and age‐specific differences in ultrasonic vocalizations

“…Similarly deviant vocalizations have also been observed in Fmr1‐ and Tsc1‐ deficient pups, therefore our results contribute to a consistency of communication deficits found across several mTOR models (Reynolds et al., 2016; Tsai et al., 2012; Young, Schenk, Yang, Jan, & Jan, 2010). Specifically, Fmr1 KO pups were shown to emit significantly fewer vocalizations than their WT counterparts when separated from their mother (Reynolds et al., 2016). In contrast, Tsc1 HT pups emitted significantly more vocalizations than their controls (Tsai et al., 2012).…”

“…Both male and female Fmr1 KO pups have been shown to exhibit a decreased call duration when compared with wild types, resembling our findings in this study (Reynolds et al., 2016). Call duration is significant as dams have been shown to prefer a longer call over a shorter one (Smith, 1976).…”

“…They can be emitted when a pup is separated from its parents, during social play, and are used during courtship and mating rituals, in addition to social investigation in adult mice (D'Amato, Scalera, Sarli, & Moles, 2005; Nyby, 1983; Panksepp et al., 2007). Research also suggests that altered USVs are an important component of the phenotype for various neurodevelopmental conditions, including ASD, Fragile X, and tuberous sclerosis complex (Reynolds, Nolan, Jefferson, & Lugo, 2016; Scattoni, Gandhy, Ricceri, & Crawley, 2008; Tsai et al., 2012). …”

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

“…[5][6][7][8][9][10] Given that the Fmr1 mutation is an X-linked mutation, females with the mutation are typically heterozygous and the functional copy of the gene is still expressed throughout the body. 18,19 These prior studies show communication alterations in male and female Fmr1 mutants, therefore helping to elucidate the impact of sex. However, when studies compare male and female mice with full loss of Fmr1, there are still sex differences in their behavioral phenotype, suggesting that gene dosage effects are not the only factor involved.…”