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

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.

UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity

“…However, to date there is no report indicating that there is decreased autophagy in AS mice, suggesting the existence of different mechanisms downstream of mTORC1 in these two different mouse models. Although mTOR signaling is increased in Fragile X mouse models, a recent report showed that chronic rapamycin treatment did not reverse behavioral phenotypes and had adverse effects on sleep and social behavior in both control and Fmr1 KO mice ( Saré et al, 2017 ). These results strengthen the notion that further understanding of the mTOR pathway and its upstream and downstream regulation is needed.…”

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

“…Although dysregulation of mTORC1 has been documented in fragile X humans (Hoeffer et al, 2012), mice (Sharma et al, 2010), and flies (Gross et al, 2015), a role for mTORC2 is, as yet, unclear. A recent finding that chronic treatment with rapamycin, which inhibits mTOR, had an adverse effect on sleep and social behavior in both control and Fmr1 KO mice (Saré et al, 2018) may simply reflect the not unexpected observation that not only too much, but also too little, mTOR activity is deleterious (Saré et al, 2018). Interestingly, mTOR dysregulation has also been observed in ASD patients with 15q11-13 duplication and in a mouse model overexpressing the Cyfip1, part of the 15q11-13 region (Oguro-Ando et al, 2015).…”

Audiogenic Seizures in theFmr1Knock-Out Mouse Are Induced byFmr1Deletion in Subcortical, VGlut2-Expressing Excitatory Neurons and Require Deletion in the Inferior Colliculus

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