Rapamycin Fails to Reverse Fragile X-related Behavior, Study in Mice Shows

Using rapamycin to rein in an overactive mTOR cell signaling pathway isn’t an effective way to treat fragile X syndrome, a study in mice indicates.

It showed that rapamycin does not reverse most behavioral characteristics of the disease, including learning and memory problems, susceptibility to seizure, and hyperactivity. And it made mice’s sleep problems and social behavior worse, researchers said.

The study, “Negative Effects of Chronic Rapamycin Treatment on Behavior in a Mouse Model of Fragile X Syndrome,” was published in the journal Frontiers in Molecular Medicine, 

Fragile X syndrome is caused by an FMR1 gene mutation that leads to lack of the FMR1 protein.

Mouse models of fragile X, known as Fmr1 KO mice, have many of the same behavioral features as humans with the disease. These includes learning and memory problems, susceptibility to seizure, hyperactivity, sleep difficulties, and social behavior problems.

Rapamycin inhibits a cell signaling pathway led by a protein called mammalian target of rapamycin, or mTOR. The pathway, which is overactive in Fmr1 KO mice, is thought to play a crucial role in fragile X.

Scientists have also linked mTOR pathway abnormalities to many neurological conditions, including austism, epilepsy, and neurodegenerative disorders.

Wondering if blocking the mTOR pathway could improve fragile X symptoms, researchers treated Fmr1 KO mice with the mTOR inhibitor rapamycin.

It significantly reduced levels of p-S6 protein, a target of the mTOR pathway that is present in high amounts in the mouse model. This indicated that rapamycin was effective at inhibiting the pathway.

Unfortunately, it did not reverse any of the mice’s fragile X-related behaviors. In fact, both their sleep and social behavior became worse than untreated Fmr1 KO mice.

In terms of social behavior, Fmr1 KO mice generally prefer to spend time with other mice rather than with an inanimate object. After receiving rapamycin, they showed no preference. This indicated a dysfunction in social behavior, researchers said.

The results prompted the team to conclude that “targeting the mTOR pathway in FXS is not a good treatment strategy and that other pathways should be considered.”

In fact, “in some respects, rapamycin is detrimental in Fmr1 KO mice,” they added.