AUTHOR=Saré Rachel M. , Song Alex , Loutaev Inna , Cook Anna , Maita Isabella , Lemons Abigail , Sheeler Carrie , Smith Carolyn B. 

TITLE=Negative Effects of Chronic Rapamycin Treatment on Behavior in a Mouse Model of Fragile X Syndrome

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=10

YEAR=2018

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2017.00452

DOI=10.3389/fnmol.2017.00452

ISSN=1662-5099

ABSTRACT=<p>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 <italic>FMR1</italic> gene. This is modeled in the mouse by deletion of <italic>Fmr1</italic> (<italic>Fmr1</italic> KO). <italic>Fmr1</italic> 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 <italic>Fmr1</italic> KO mice and is thought to be important for the pathogenesis of this disorder. We treated <italic>Fmr1</italic> 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 <italic>Fmr1</italic> 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 <italic>Fmr1</italic> 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.</p>