Closing in on Rett syndrome

Study shows that location in the brain matters when it comes to the syndrome

Normal 0 false false false MicrosoftInternetExplorer4 A study released in the Sept. 25 Neuron is a major step toward identifying the brain regions behind the behaviors that characterize Rett syndrome, a debilitating, autism-like neurological disease that primarily affects females.

The syndrome is marked by a constellation of symptoms, the most striking of which is repetitive hand wringing. Behavioral symptoms of the syndrome include a lack of language skills, muscle rigidity that imparts a characteristic tremor, high anxiety and, in some cases, excessive aggression.

Rett syndrome is caused by a damaged copy of a gene called MeCP2, which is located on the X chromosome. Because the gene is expressed throughout the brain, finding the discrete regions that control the long list of individual behavioral symptoms associated with the syndrome has proven exceptionally hard.

For help, scientists have turned to mice. Animals lacking the protein MeCP2 in all brain regions behave similarly to people who have Rett syndrome: increased stress responses, as measured by high levels of a stress hormone, muscle abnormalities and a distinct tremor. Presumably, each of these symptoms could be traced back to a particular region of the mouse brain, but because these mice lack MeCP2 everywhere, which region or regions were responsible for the abnormal behaviors was anyone’s guess.

A research team headed by Huda Zoghbi, a Howard Hughes Medical Institute researcher at Baylor College of Medicine in Houston, has narrowed the search through precise brain manipulations in mice. 

To home in on one region of the brain, Zoghbi’s team bred mice that were missing the gene only in the hypothalamus. In people, this region of the brain is critical for regulating not only emotions but also basic functions, such as blood pressure, breathing and sleep cycles. The team then put the mice through a battery of physical and mental tests. 

While targeting a mutation to a small population of neurons is painstaking, the procedure provides clear benefits. “You get to see something that is masked. You really know what these neurons are doing specifically in a location,” explains Zoghbi.

What the researchers saw was surprising: These mice showed several — but not all — of the abnormal behaviors shown by the mice lacking MeCP2 throughout the brain. Specifically, the mice’s stress responses were higher than normal, and their aggression levels were greater in unfamiliar conditions. 

When the mice were housed with familiar litter-mates, they behaved normally. However, when presented with a strange mouse — a so-called intruder — the mice lacking MeCP2 specifically in the hypothalamus reacted with significantly more tail rattling and attacks.

“It’s really the adaptation to a stranger in a new social domain that gets them frazzled,” says Zoghbi.

That the mice only act aggressively in unfamiliar situations is interesting in light of reports that patients with autism-spectrum disorders often react to stressful and unusual conditions with aggression, the research group concludes.

Lisa Monteggia, a psychiatrist at the University of Texas Southwestern Medical Center at Dallas who is familiar with Rett syndrome, says, “I think this is a useful approach to try and map out regions of the brain that mediate complex behaviors.”

Granted, a tail-rattling mouse is a far cry from autism spectrum behaviors in humans. But studies like this are moving incrementally closer to the daunting task of understanding how brain regions and neurons — and the genes expressed inside them — influence behavior, and importantly, what to do when something goes wrong.  “Slowly and surely, we will get there,” Zoghbi says.

Laura Sanders is the neuroscience writer. She holds a Ph.D. in molecular biology from the University of Southern California.

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