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New Findings May Lead To Treatment For Anxiety In Rett Syndrome

Date:
November 17, 2006
Source:
Rett Syndrome Research Foundation
Summary:
The classic form of Rett Syndrome shows us a child who is the picture of anxiety: she wrings her hands, hyperventilates, trembles. The progression of the disorder includes loss of acquired skills, speech and mobility. Many girls with Rett display elevated stress hormones. New studies may shed light on whether much of the anxiety of these children is a response to the experience of Rett, or is an intrinsic aspect of the disorder.

The classic form of Rett Syndrome (RTT) shows us a child who is the picture of anxiety: she wrings her hands, hyperventilates, trembles. The sinister progression of the disorder, which usually begins to manifest between the ages of 6-18 months, includes loss of acquired skills, speech and mobility, sometimes an autistic-like withdrawal, sometimes months of inconsolable crying. A majority of girls with RTT, which is caused by mutations in the gene MECP2, display elevated stress hormones measured by urinary cortisol levels. New studies may shed light on whether much of the anxiety of these children is a response to the subjective experience of RTT, or is an intrinsic aspect of the disorder.

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The lab of Huda Zoghbi at Baylor College of Medicine has been studying anxiety in their mouse model of the syndrome. These MeCP2308 mice, so called because they bear a mutant version of the MeCP2 protein that is truncated prematurely (at amino acid 308), have numerous characteristics that mimic human RTT. They appear to be healthy early on in life, but within several weeks of birth develop tremors, spasticity, seizures, and begin to display impairments in social behavior and cognitive skills. They also show signs of anxiety: they huddle in closed spaces rather than curiously exploring new areas, they avoid spending time with other animals, they tremble noticeably when being handled by the gentlest of researchers. And, as the Zoghbi lab now reports in The Proceedings of the National Academy of Sciences, the mice produce high levels of corticosterone, the mouse equivalent of the human stress hormone.

What causes the mice to be so stressed? Because MECP2 controls the expression of other genes, mutations in the protein that disrupt its normal function should allow misexpression of target genes. Thus far, five targets of MeCP2 activity have been identified, though the precise role any of them play in the RTT phenotype remains unclear. But the combination of anxious behavior and increased corticosterone release led McGill et al. to hypothesize that their mice might be suffering from abnormal expression of Crh, the gene that produces corticotropin-releasing hormone (CRH). The authors searched specific regions of the MeCP2308 mouse brain where CRH normally works, and found that the mice do indeed overexpress Crh in regions responsible for behavioral and physiological responses to stress.

In healthy mammals, CRH activates the hypothalmic-pituitary-adrenal axis in response to stressful events, stimulating glucocorticoid release from the adrenal cortex. When the environmental stressor subsides, glucocorticoid levels return to normal. Chronic stress, however, can damage neurons, reduce synaptic plasticity, and impair short-term memory -- as any stressed-out parent can attest. What is interesting here is that these same neuronal effects are seen in RTT. This suggests that an overabundance of CRH could be contributing to other aspects of the Rett phenotype.

The good news is that it is now possible to envision finding a drug that would reduce anxiety in individuals with RTT by blocking receptors for corticotropin-releasing hormone. Decreasing anxiety might also reduce some other symptoms of RTT that are produced by chronic neuronal exposure to CRH.

Funding for this research came from the National Institutes of Health, the National Library of Medicine, the Keck Center for Computational and Structural Biology, the National Center for Research Resources, the Mental Retardation and Developmental Disabilities Research Center and the Howard Hughes Medical Institute.


Story Source:

The above story is based on materials provided by Rett Syndrome Research Foundation. Note: Materials may be edited for content and length.


Cite This Page:

Rett Syndrome Research Foundation. "New Findings May Lead To Treatment For Anxiety In Rett Syndrome." ScienceDaily. ScienceDaily, 17 November 2006. <www.sciencedaily.com/releases/2006/11/061116121435.htm>.
Rett Syndrome Research Foundation. (2006, November 17). New Findings May Lead To Treatment For Anxiety In Rett Syndrome. ScienceDaily. Retrieved December 22, 2014 from www.sciencedaily.com/releases/2006/11/061116121435.htm
Rett Syndrome Research Foundation. "New Findings May Lead To Treatment For Anxiety In Rett Syndrome." ScienceDaily. www.sciencedaily.com/releases/2006/11/061116121435.htm (accessed December 22, 2014).

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