Abstract
Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is also highly associated with autism spectrum disorders (ASD). It is caused by expansion of a CGG repeat sequence on the X chromosome resulting in silencing of the FMR1 gene. This is modeled in the mouse by deletion of Fmr1 (Fmr1 KO). Fmr1 KO mice recapitulate many of the behavioral features of the disorder including seizure susceptibility, hyperactivity, impaired social behavior, sleep problems, and learning and memory deficits. The mammalian target of rapamycin pathway (mTORC1) is upregulated in Fmr1 KO mice and is thought to be important for the pathogenesis of this disorder. We treated Fmr1 KO mice chronically with an mTORC1 inhibitor, rapamycin, to determine if rapamycin treatment could reverse behavioral phenotypes. We performed open field, zero maze, social behavior, sleep, passive avoidance, and audiogenic seizure testing. We found that pS6 was upregulated in Fmr1 KO mice and normalized by rapamycin treatment, but, except for an anxiogenic effect, it did not reverse any of the behavioral phenotypes examined. In fact, rapamycin treatment had an adverse effect on sleep and social behavior in both control and Fmr1 KO mice. These results suggest that targeting the mTOR pathway in FXS is not a good treatment strategy and that other pathways should be considered.
Highlights
Fragile X syndrome is the most common inherited form of intellectual disability
Increased mTOR complex 1 (mTORC1) Activity in Fmr1 KO Mice Normalized by Chronic Rapamycin Treatment
We found that Fmr1 KO mice have increased levels of p-S6, and that rapamycin reverses this phenotype
Summary
Fragile X syndrome is the most common inherited form of intellectual disability It is an X-linked disorder caused by an elongation of a CGG repeat (>200) in the 5 -untranslated region of the FMR1 gene leading to silencing of the gene and a paucity of the protein product FMRP (Verkerk et al, 1991). In a mouse model of FXS, Fmr KO, behavioral characteristics paralleling those seen in FXS individuals have been demonstrated. These include hyperactivity, decreased preference for social novelty, sleep deficits, and learning and memory deficits (Mineur et al, 2002; Qin et al, 2002; Kooy, 2003; Spencer et al, 2005; Liu et al, 2011; Kazdoba et al, 2014; Saré et al, 2016, 2017)
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