Deficient Sleep in Mouse Models of Fragile X Syndrome

Abstract

In patients with fragile X syndrome (FXS), sleep problems are commonly observed but are not well characterized. In animal models of FXS (<i>dfmr1</i> and <i>Fmr1</i> knockout (KO)/<i>Fxr2</i> heterozygote) circadian rhythmicity is affected, but sleep <i>per se</i> has not been examined. We used a home-cage monitoring system to assess total sleep time in both light and dark phases in <i>Fmr1</i> KO mice at different developmental stages. <i>Fmr1</i> KOs at P21 do not differ from controls, but genotype × phase interactions in both adult (P70 and P180) groups are statistically significant indicating that sleep in <i>Fmr1</i> KOs is reduced selectively in the light phase compared to controls. Our results show the emergence of abnormal sleep in <i>Fmr1</i> KOs during the later stages of brain maturation. Treatment of adult <i>Fmr1</i> KO mice with a GABA_B agonist, R-baclofen, did not restore sleep duration in the light phase. In adult (P70) <i>Fmr1</i> KO<i>/Fxr2</i> heterozygote animals, total sleep time was further reduced, once again in the light phase. Our data highlight the importance of the fragile X genes (<i>Fmr1</i> and <i>Fxr2</i>) in sleep physiology and confirm the utility of these mouse models in enhancing our understanding of sleep disorders in FXS.