New Understanding of Fragile X Syndrome Points to New Treatment Possibilities

New Understanding of Fragile X Syndrome Points to New Treatment Possibilities

Posted: December 17, 2012

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From The Quarterly, Fall 2012

Supported with a NARSAD Independent Investigator Grant, an international team of scientists has made critical new discoveries about which brain dysfunctions cause Fragile X Syndrome and how it may be possible to correct them. FragileX syndrome is the devastating illness often associated with mental retardation that is caused by a genetic mutation (FMR-1). It is also the most commonly known genetic cause of autism.

This important study was co-led by 2010 NARSAD Independent Investigator Grantee, Olivier J. Manzoni, Ph.D., of INSERM (Institut National de la Santé et de la Recherche Médicale) in France and 2005 and 2009 NARSAD Distinguished Investigator Grantee, Daniele Piomelli, Ph.D., of the University of California, Irvine.

As detailed in an article published in Nature Communications in late September, the Piomelli-Manzoni team performed several sets of experiments to obtain their news-making results. In one phase of their work, they looked at mice with the genetic FMR-1 mutation and its corresponding lack of a protein called FMRP. The lack of this protein causes Fragile X in humans. They found that, together with the missing protein, a type of activity called long-term depression (LTD) was absent at synapses that link neurons in two critical parts of the brain, the ventral striatum and prefrontal cortex.

They also discovered that this synaptic dysfunction affected the transmission of endocannabinoid signals in the brain. Without them, electrical signals at synapses are further compromised. And, indeed, in Fragile X syndrome, problems in synaptic communication are known to be associated with cognitive and behavioral problems.

After making these discoveries, Drs. Piomelli, Manzoni and colleagues sought to determine if they could artificially enhance or promote the impaired endocannabinoid-system signals. They found that pharmacological enhancement of such signaling normalizes the problem at excitatory synapses and corrects behavioral abnormalities in mice lacking the FRMP protein—a model for human Fragile X syndrome.

Dr. Piomelli stresses that this does not mean a cure for either Fragile X or autism is imminent. But the new study opens a new horizon of understanding on biological processes that are now demonstrated to be capable of causing Fragile X. That means a distinctly new path of research can be pursued so that more details can be learned that point toward the development of new treatments.

“What we do hope on the basis of this work,” says Dr. Piomelli, “is that we will one day be able to increase the ability of people with Fragile X syndrome to socialize and engage in normal cognitive functions.” Dr. Piomelli has been supported throughout his career with NARSAD Grants, starting with a NARSAD Young Investigator Grant in 1988.