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By blocking a single brain chemical, many of the psychiatric and neurological disabilities associated with a primary cause of mental retardation could be treated, according to MIT neuroscientist Mark Bear in the July issue of Trends in Neuroscience.
The findings of Bear, the Picower Professor of Neuroscience at the Picower Center for Learning and Memory at MIT, and his colleagues from the University of Texas and Emory University School of Medicine have given hope to parents Katie Clapp and Mike Tranfaglia of West Newbury, Mass.
"This research offers the possibility of what I've only dared to dream but have been working toward for 10 years--a specific treatment that will help my son and hundreds of thousands of other children and adults with fragile X," said Clapp. "It offers the hope that a single medication could combat my son's seizures, panic, hyperactivity, and perhaps even enable him to live independently one day."
Clapp and Tranfaglia are founders of FRAXA Research Foundation, a Newburyport, Mass.-based nonprofit organization devoted to finding a cure to fragile X. The couple has a 14-year-old son with fragile X syndrome and a 12-year-old daughter who is a carrier. FRAXA is one of the organizations funding Bear's research.
Fragile X syndrome is the leading known inherited cause of mental retardation. The condition, tied to a mutated gene on the X chromosome, has effects ranging from mild learning disabilities to severe autism. Fragile X syndrome's neurological and psychological symptoms include anxiety and obsessive-compulsive behavior, a heightened sensitivity to touch and in some cases, a tendency toward epileptic seizures. Other physical symptoms include a high arched palate, lazy eye, large ears, a long face, poor muscle tone, loose bowel movements and flat feet. There are significant social and health care costs associated with treatment, special education and lost income for those who are affected.
Scientists are focusing on the molecular changes in the brain and body that result from the single mutated gene and fragile X retardation protein (FMRP), its resulting lost protein.
FMRP's job is to help messenger RNA translate the genetic code for new proteins that are continually synthesized in the synapses between brain cells. The proteins are the building blocks that shape the synapses that allow brain cells to communicate. Without FMRP, proteins are misregulated and cells can't "talk to" each other normally.
"One reason for the sudden interest is that FMRP has proven to be a fascinating molecule; it has captured the attention of neurobiologists interested in the synaptic control of protein synthesis that, in turn, changes synaptic structure and function," wrote Bear, who is also a Howard Hughes Medical Institute investigator.
There is growing evidence that there is a connection between the loss of FMRP and one of the brain's chief network managers--the metabotropic glutamate receptors (mGluRs). There are three groups of mGluRs with eight subtypes, all interacting with glutamate in different ways. MGluRs are implicated in a variety of diseases such as epilepsy, Parkinson's and Huntington's disease. They also may play a role in pain, schizophrenia and anxiety. The key mGluRs implicated in the new theory are mGluR1 and mGluR5.
Bear's work provides evidence that a drug blocking mGluR5 might effectively treat fragile X symptoms in adults. If it turns out that the syndrome appears in children whose brains developed with too much mGluR signaling, then early intervention with an mGluR-inhibiting drug may prevent some of the symptoms from appearing at all.
"Even the most skeptical would agree it is astonishing that a single compound could target such disparate symptoms of Fragile X syndrome as epilepsy, anxiety, hypersensitivity to touch and loose bowels," Bear said.
Building new connections
Glutamate, the main neurotransmitter in the brain, helps neurons communicate. MGluRs respond to glutamate by activating proteins inside brain cells and fine-tuning the signals sent between cells to maintain balance in neuronal activity. Activation of glutamate receptors is responsible for two key brain processes called long-term potentiation (LTP) and long-term depression (LTD), which many believe are the basis for learning and memory. LTP helps build new connections among brain cells and LTD helps destroy unneeded connections.
Bear says that the lack of FMRP seems to lead to overactive signaling of mGluR5, which in turn leads to too much LTD, which can slow the maturation of synapses by tipping the balance from synapse gain to synapse loss during a critical period of brain development.
Overactive signaling by mGluR5 could contribute to many of the symptoms of fragile X.
The receptor is found in many different parts of the nervous system, where it has different functional roles. Inhibiting mGluR5 in the brain reduces anxiety and susceptibility to seizures; in the gut, inhibiting the receptors reduces bowel motility; in the skin, it produces analgesia.
A chemical called 2-methyl-6-(phenylethynyl)-pyridine inhibits mGluR5 receptors and is being used on mice to test the new theory. Bear is a founder and chairman of the scientific advisory board of Sention, a pharmaceutical development company in Providence, R.I. Sention has licensed the rights to develop a drug based on this new research, and hopes to be able to test this class of compounds in humans once critical preclinical research is successfully completed.
"We are evaluating opportunities to develop a new drug for treatment of humans with fragile X syndrome. We anticipate this process could take anywhere from 18 to 24 months before we are ready to apply to the FDA for permission to begin clinical testing in humans," Sention CEO Randall Carpenter said.
In addition to Bear, authors of the Trends in Neuroscience paper are Kimberly M. Huber of the Center for Basic Neuroscience at University of Texas Southwestern Medical Center in Dallas and Stephen T. Warren of Emory University School of Medicine in Atlanta.
This work is supported by the FRAXA Research Foundation and the National Institute for Child Health and Human Development.