Altered Sleep in Fragile X Syndrome: Basis for a Potential Therapeutic Target

With a $45,000 grant from FRAXA Research Foundation, Dr. Carolyn B. Smith and Dr. Rache Sare at the National Institute of Mental Health investigated the basis of sleep problems in Fragile X syndrome.

$45,000 Grant
Rachel Sare, PhD
Postdoctoral Fellow
Carolyn B. Smith, PhD
Principal Investigator
National Institute of Mental Health
2016 FRAXA Research Grant
We hypothesize that sleep abnormalities contribute to behavioral abnormalities in Fragile X syndrome, and we propose that treatment strategies should include a focus on normalizing sleep patterns.  Our long-term goal is to identify potentially modifiable risk factors contributing to symptoms of FXS. Our objective is to determine the extent to which social behavior abnormalities, hyperactivity, and learning impairments are improved when sleep is improved in a mouse model of FXS. If improving sleep improves behavior, we propose that treatment of sleep may be a novel therapy for FXS that may be used alone or in combination with other proposed therapies.

Previous Grant:

Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Fragile X Syndrome

National Institute of Mental Health
20005 FRAXA Research Grant

Several lines of evidence support the idea that Fragile X syndrome may involve a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Hessl et al. (Psychoneuroendocrinology 27:855-872, 2002) reported that boys with Fragile X syndrome have elevated levels of cortisol in saliva under both normal and stressful circumstances.

We have found in the Fragile X (Fmr1 null) mouse increased rates of cerebral protein synthesis and abnormal spine morphology in hypothalamic nuclei. Julie Lauterborn (Mol Brain Res 131:101-109, 2004) reports prolonged recovery from stress-induced c-fos expression in hypothalamic nuclei in Fmr1 null mice. Our proposal is to study the HPA axis in Fmr1 null mice. We will examine its normal function, its response to and recovery from stress, and its feedback regulation. Our experiments are designed to address the hypothesis that there is an impairment of feedback regulation of the HPA axis in Fragile X patients. If so, our results will begin to localize the step(s) at which regulation is impaired.

Understanding of an impairment of the HPA axis in Fragile X and the specific step(s) at which the impairment occurs may lead to targeted therapies that could help to alleviate symptoms of the disease.

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