Prepartum bumetanide treatment reverses altered neonatal social communication but nonspecifically reduces postpubertal social behavior in a mouse model of fragile X syndrome

Fragile X syndrome is caused by monogenic silencing of the <i>FMR1</i> gene and is characterized by high rates of autism spectrum disorder. A previous study demonstrated that prepartum administration of bumetanide, a chloride transporter blocker, normalized neonatal vocalization in non-congenic <i>Fmr1</i> knockout (KO) pups. However, the genuine contribution of <i>Fmr1</i> deletion to this phenotype in a congenic <i>Fmr1</i> KO mouse model and the long-lasting effect of prepartum bumetanide administration on postpubertal social interaction remains unclear. The current study aimed to determine the impact of prepartum bumetanide administration on vocalization at postnatal day 7 and social interaction at 6 and 8 weeks of age in a congenic <i>Fmr1</i> KO mouse model in which the genetic backgrounds were homogeneous between KO and wild-type (WT) littermates. Moreover, we applied a computational analytical algorithm and determined predictive variables of neonatal vocalization for postpubertal social interaction. Our data showed that (1) KO mice exhibited altered numbers and sequences of distinct call types during neonatal vocalization and reduced social interaction at 6 weeks, (2) select sets of neonatal vocalization variables predicted postpubertal social interaction levels, and (3) bumetanide restored neonatal vocalization in KO pups but nonspecifically reduced social interaction in WT and KO mice at 6 weeks. These data indicate that <i>Fmr1</i> deletion selectively impacts distinct elements of neonatal vocalization and postpubertal social interaction. Additionally, bumetanide selectively restores neonatal vocalization but has a transient nonspecific negative impact on subsequent postpubertal social interaction.