Selective Deletion Of Rett Syndrome Gene Provides Insight Into Origin Of Complex Behaviors

Main Category: Autism
Also Included In: Genetics;  Neurology / Neuroscience;  Psychology / Psychiatry
Article Date: 25 Sep 2008 - 6:00 PDT

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A new study describes an exciting approach for mapping the specific neuronal origins of complex and varied behaviors characteristic of Rett syndrome (RTT), an autism spectrum disorder. The research, published by Cell Press in the September 25th issue of the journal Neuron, also uncovers a novel and unexpected role for the gene that causes RTT.

RTT is a devastating neurological disorder associated with a broad array of abnormalities that impact almost every part of the nervous system. The majority of RTT cases are caused by mutations in the methyl-CpG-binding protein (MECP2) gene, which encodes MeCP2, a protein widely expressed throughout the brain. In addition to classic RTT, patients with MECP2 mutations exhibit a wide variety of neuropsychiatric disorders, including autism, juvenile onset schizophrenia, and bipolar disease with mental retardation.

"Creation of several mouse models carrying different Mecp2 mutations has enabled recapitulation of many of the manifestations seen in patients and has enhanced our appreciation of the breadth of clinical phenotypes that are associated with RTT," says senior study author Dr. Huda Y. Zoghbi from the Howard Hughes Medical Institute and Baylor College of Medicine. Dr. Zoghbi and colleagues proposed that particular RTT phenotypes may result from loss of MeCP2 function in specific neurons and that deleting Mecp2 from small groups of neurons in the mouse brain may enable mapping of specific neurobehavioral phenotypes to discrete brain regions or cell types.

"We focused on a region of the brain called the hypothalamus because patients with MECP2 mutations display many phenotypes suggestive of hypothalamic dysfunction, such as sleep abnormalities and heightened anxiety as well as gastrointestinal, breathing, and cardiac abnormalities," explains Dr. Zoghbi.

The researchers performed behavioral and physiological tests on mice lacking Mecp2 in a subset of hypothalamic neurons (known as Sim1 neurons) and found that the mice displayed some of the characteristics observed in RTT patients, such as an increased physiological response to stress.

Unexpectedly, they also uncovered a previously unknown role for MeCP2 in the regulation of social and feeding behaviors, as loss of MeCP2 in hypothalamic neurons resulted in mice that were aggressive and obese. Interestingly, the mice were aggressive only when put in a novel social situation, reminiscent of the aggression seen in some patients with autism spectrum disorders. Probing the cause of obesity, the investigators found that mice lacking MeCP2 in Sim1 hypothalamic neurons did not seem to know when to stop eating.

"Our study suggests that conditional deletion of Mecp2 in different cell populations or different regions of the brain will enable us to map the neuroanatomical origins of the complex behaviors and phenotypes seen in RTT and MeCP2 disorders," explains Dr. Zoghbi. "The more restrictive we are in choosing the neurons in which to delete Mecp2, the more we will learn about the function of MeCP2 in specific neurons; take this study for example, who would have thought that MeCP2 regulates the amount of food we ingest!"

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The researchers include Sharyl L. Fyffe, Baylor College of Medicine, Houston, TX; Jeff L. Neul, Baylor College of Medicine, Houston, TX; Rodney C. Samaco, Baylor College of Medicine, Houston, TX; Hsiao-Tuan Chao, Baylor College of Medicine, Houston, TX; Shay Ben-Shachar, Baylor College of Medicine, Houston, TX; Paolo Moretti, Baylor College of Medicine, Houston, TX; Bryan E. McGill, Baylor College of Medicine, Houston, TX; Evan H. Goulding, University of California, San Francisco, San Francisco, CA; Elinor Sullivan, University of California, San Francisco, San Francisco, CA; Laurence H. Tecott, University of California, San Francisco, San Francisco, CA; and Huda Y. Zoghbi, Baylor College of Medicine, Houston, TX, Howard Hughes Medical Institute.

Source: Cathleen Genova
Cell Press

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