Faulty Neurotransmitter System May Contribute to Rett Syndrome, Autism, and Other Disorders

A new study has pinned some of the symptoms of Rett syndrome—a disease of the nervous system that impairs movement, communication, and coordination—to a set of neurons that usually work to rein in nerve cell firing activity in the brain. The new clues to the disorder’s underlying cellular and biochemical causes offer researchers a potential therapeutic target.

Mild cases of Rett syndrome can look a lot like autism; the most severe cases cause breathing difficulties and early death. The genetic mutation responsible for Rett syndrome occurs in a gene called MECP2, which produces a protein that nerve cells need to function normally. Rett syndrome almost exclusively affects girls, because the MECP2 gene is carried on the X chromosome. Boys who are born with a mutation in MECP2 usually die within months after birth, because they have only one X chromosome and thus one copy of the gene. In girls, an intact MECP2 gene on one X chromosome can partially compensate for a MECP2 mutation on their other X chromosome, producing a healthy protein in at least 50 percent of their brain cells. But no one really understood the role of the MeCP2 protein in disease, nor why it leads to so many neurological symptoms including autism-like symptoms.

In a paper published in the November 11, 2010, issue of Nature, Howard Hughes Medical Institute (HHMI) scientists show that much of the dysfunction can be traced to a shortage of a signaling molecule called GABA, and that the reduction of GABA in certain groups of neurons determines specific manifestations of the disease.

“Patients who don’t have full-blown Rett syndrome tend to have fewer cells with the mutated protein. Sometimes we see a learning disability, sometimes autism, sometimes obsessive-compulsive behavior,” says lead researcher Huda Zoghbi, an HHMI investigator at Baylor College of Medicine. “It led us to think that each time we see different features, it may be because [the X chromosome with the gene mutation] is active different populations of neurons.”

Using a procedure and reagents developed by Rockefeller University scientist and fellow HHMI investigator Nathaniel Heintz, Zoghbi and graduate student Hsiao-Tuan Chao engineered a mouse that allowed them to delete the MeCP2 protein selectively from GABA-expressing neurons.

When the researchers examined the animals’ behavior and physiology, they found that eliminating MeCP2 from GABA neurons, which make up about 15 to 20 percent of all neurons, was enough to cause many Rett syndrome features as well as autism-like behaviors, including forepaw-clasping, self-injury, and compulsive behaviors such as excessive grooming.

Zoghbi and her colleagues wanted to know why this selective elimination of MeCP2 was having this effect. A closer look revealed that the protein seemed to be affecting enzymes that produce the neurotransmitter GABA, a molecule that activates inhibitory neurons that are dedicated to preventing neural overactivity. Levels of those enzymes, and the GABA they make, were all reduced by 30 percent in the mice with reduced MeCP2. As a result, while excitatory neural activity stayed the same, the inhibitory neurons could no longer keep nerve signals in balance. The disparity allowed for hyper-repetitive and compulsive behaviors, altered social behavior, motor abnormalities, and learning deficits.

Because the new mouse model provided Zoghbi and her colleagues such precise control over MeCP2 production, they were able to more closely pinpoint which areas of the brain were responsible for specific disease-related actions. When they removed the gene only in the mice’s forebrain GABA neurons, leaving all other protein production intact, they found that the autism-like behaviors and motor abnormalities remained. But they completely eliminated the breathing defects and premature death that are present only when MeCP2 is eliminated from both forebrain and hindbrain GABA neurons..

“This taught us about the importance of these inhibitory neurons in neuropsychiatric disorders,” Zoghbi says, saying that her team’s findings could have implications for not just autism and Rett syndrome, but more specific conditions like obsessive-compulsive disorder.

“We were surprised to find that many features of Rett syndrome can be accounted for by a disturbance in the GABA inhibitory neurons,” she says. It remains to be seen whether enhancing GABA could rescue neural function in Rett mouse models that lack the protein in many neuronal types, but Zoghbi says the findings offer researchers a new strategy to pursue in developing potential treatments. “It gives you a path forward,” she says. “If you can improve GABA signaling pharmacologically, you might improve features of Rett syndrome.”