New Insight About The Source Of Anxiety In Rett Syndrome

"This is one of the first symptoms that we can link to a molecular cause," said Dr. Huda Zoghbi, professor of pediatrics, neurology and molecular and human genetics at Baylor College of Medicine and a Howard Hughes Medical Institute investigator. "Rett affects many parts of the nervous system, and patients have many symptoms; but we don't know if they happen all at once or if there is a cascade of events."

If the latter is true, then physicians might be able to intervene by halting or limiting the effect of the first symptoms to prevent secondary effects such as those that occur due to chronic anxiety.

The mouse model of Rett was developed in Zoghbi's laboratory where scientists also found that a mutation in the gene MeCP2 (methyl-CpG-binding protein 2) causes the disorder. Between the ages of six and 18 months, children with this disease become mentally retarded, wring their hands, have difficulty walking and breathing, and suffer from anxiety. The severity of the symptoms varies with the person.

"MeCP2 is a master regulator of other genes, like a foreman in a factory," said Bryan E. McGill, a BCM M.D./Ph.D. student studying in Zoghbi's laboratory. "Considered by itself, it cannot tell you about the molecular changes that lead to the phenotype (symptoms) we see in the children. Our goal has been to find the intermediaries in the process. We want to know what other genes MeCP2 is controlling. Then we have a better understanding of the molecular basis of the phenotype we see in children."

In their work, they found that CRH (corticotropin-releasing hormone) plays a critical role in the stress response that produces anxiety in these children, governing in part the production of stress hormones. In humans, the major one of these is cortisol. In mice, it is corticosterone.

They chose anxiety because it has been well studied, and its molecular basis is partially understood. They found that the Rett mice suffered from serious anxiety and that in a stressful situation, they produced 1.5 times the amount of corticosterone produced by normal mice.

They propose that normally, MeCP2 acts like a rheostat that controls CRH and thus the stress response, depending on the need of the situation. CRH kicks the response up. When MeCP2 is mutated, this process is less controlled.

Currently, some anti-anxiety drugs are being developed that block the receptor for CRH on the cell. McGill, Zoghbi, and their colleagues are studying the effect of these drugs on the animals with the mutated MeCP2 gene.

Others who took part in the research included Drs.Sharyl F. Bundle, Murat B. Yaylaoglu, James P. Carson, and Christina Thaller, all of BCM.

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.