New data uncover common molecular pathways between Rett syndrome, autism and schizophrenia

November 10, 2010

The laboratory of Huda Zoghbi, where the discovery that mutations in the gene MECP2 cause the severe childhood neurological disorder Rett Syndrome was made, has taken yet another step toward unraveling the complex epigenetic functions of this gene, implicated also in cases of autism, bipolar disease and childhood onset schizophrenia. The November 11 issue of Nature reports that removing MECP2 from a small group of neurons that typically make the inhibitory neurotransmitter, GABA, recapitulates many symptoms of Rett as well as numerous neuropsychiatric disorders.

The identification of the genetic basis of Rett allowed the development of a number of mouse models of the disorder, accurately reproducing the range of symptoms seen in humans. These are considered to be among the best existing models of neurological disease.

While removing MECP2 from every cell results in full-blown Rett symptoms, the Zoghbi lab during the past few years has been using genetic tools to knock out the gene from distinct subsets of specialized brain cells called neurons, in an attempt to correlate certain neuronal populations with specific symptoms.

GABA (gamma amino butyric acid) is the main inhibitory neurotransmitter in the brain. Neurons releasing GABA regulate the nervous system by acting like traffic lights on the brain's information highway. Zoghbi and Hsiao-Tuan Chao, a postdoctoral fellow in the lab and lead author of the study, use this analogy to describe the action of GABA in allowing for a balanced level of neuronal activity by controlling the strength and timing of information transfer. Surprisingly, Zoghbi, Chao and colleagues found that removing MeCP2 from the small number of GABA-producing neurons reduced production of the neurotransmitter by about 30%. This reduction reproduced many symptoms of Rett including the paw-clasping that mimics the classical hand-wringing stereotypies. After a brief period of apparently normal development, the mice display brain hyperexcitability, impaired respiration, and loss of muscle control and strength and premature lethality. Learning, memory and sensory responses are also altered. Interestingly, the mice engaged in repetitive movements reminiscent of compulsive behavior seen in a number of neuropsychiatric disorders.

The study raises a number of important points. It implicates GABA as a key player in Rett and suggests that boosting the activity of GABA producing neurons may help to alleviate the severity of some symptoms. It also begs the question: If a 30% reduction in GABA causes Rett symptoms, could a more subtle perturbation of 10% or 20% lead to certain neuropsychiatric disorders? This study suggests a possible pathway which can now be explored to answer the question fully.

"This study revealed to us the critical role of MECP2 in modulating the levels of GABA in inhibitory neurons and pinpointed all the neuropsychiatric symptoms that develop when the function of inhibitory neurons is compromised. Identifying the cellular and chemical basis of such symptoms is a first step in efforts aimed at understanding and, one day, treating such disorders," said Zoghbi.

Dr. Zoghbi, who was first drawn into Rett research through her clinical experience at Baylor College of Medicine, is a Howard Hughes investigator and a Rett Syndrome Research Trust Scientific Advisor.

Monica Coenraads, Executive Director at the Rett Syndrome Research Trust which helped to fund this work, says "The field of Rett research has benefited incalculably from Huda Zoghbi's dedication and perseverance. Her latest results suggest that GABAergic pathways are ripe for exploration not only as therapeutic intervention for Rett Syndrome but also for a much wider class of neurological disease."
About Rett Syndrome

Rett Syndrome strikes little girls almost exclusively, with first symptoms usually appearing before the age of 18 months. These children lose speech, motor control and functional hand use, and many suffer from seizures, orthopedic and severe digestive problems, breathing and other autonomic impairments. Although some victims of Rett Syndrome do not survive childhood, most live to become adults who require total, round-the-clock care.

About Rett Syndrome Research Trust

The Rett Syndrome Research Trust is the premier organization devoted exclusively to promoting international research on Rett Syndrome and related MECP2 disorders. The goal is clear: to heal children and adults who will otherwise suffer from this disorder for the rest of their lives. With experience and tight focus, RSRT has an unparalleled knowledge base and extensive networking abilities in the world of high level research. RSRT is in a unique position to stimulate, evaluate, support and monitor ambitious and novel scientific projects.

About Baylor College of Medicine

Baylor College of Medicine ( in Houston is recognized as a premier academic health science center and is known for excellence in education, research and patient care. It is the only private medical school in the greater southwest and is ranked as one of the top 25 medical schools for research in U.S. News & World Report. BCM is listed 13th among all U.S. medical schools for National Institutes of Health funding, and No. 2 in the nation in federal funding for research and development in the biological sciences at universities and colleges by the National Science Foundation. Located in the Texas Medical Center, BCM has affiliations with eight teaching hospitals, each known for medical excellence. Currently, BCM trains more than 3,000 medical, graduate, nurse anesthesia, and physician assistant students, as well as residents and post-doctoral fellows. BCM is also home to the Baylor Clinic, an adult clinical practice that includes advanced technologies for faster, more accurate diagnosis and treatment, access to the latest clinical trials and discoveries, and groundbreaking healthcare based on proven research.

Rett Syndrome Research Trust

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to