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Compound Eases Autism Behaviors in Mice

April 25, 2012

A compound that inhibits the brain chemical glutamate reduced repetitive behaviors and partially improved sociability in mouse models of autism. Though preliminary, the findings represent an important advance in autism research because they are the first to show consistent benefits from a pharmaceutical agent across two core symptoms.

The study, published online today in Science Translational Medicine, resulted from an innovative private-public collaboration that brought together researchers from the National Institutes of Health and Pfizer Worldwide Research and Development, with the goal of opening a path for autism drug discovery.

“This study has the potential to impact the direction of development for a class of experimental medicines already in clinical trials,” says Robert Ring, Ph.D., who helped initiate the collaborative research project while working for Pfizer. Ring is now vice president for translational research with Autism Speaks. “The results provide encouragement that the reduction of core symptoms in autism may also be addressed, even assisted, with medical interventions.”

Glutamate is one of the brain’s most important excitatory, or stimulating, nerve signal transmitters. It is known to be abundant in brain nerve cells involved in repetitive and social behaviors. In addition, several genes associated with autism produce proteins that affect how glutamate regulates the actions of brain cells, or neurons.

In this study, researchers at the NIH and Pfizer investigated the biologically active Pfizer compound GRN-529, which reduces the effects of glutamate in neurons. GRN-529 is similar to other glutamate-inhibiting compounds already in human clinical trials for other disorders, including fragile X syndrome, whose symptoms include autism behaviors.

The investigators tested the compound in two strains of mice with behaviors that reflect the core symptoms of autism. One strain shows decreased social interactions and abnormal repetitive self-grooming, while the other jumps over and over again in vertical leaps.

A single dose of GRN-529 significantly reduced repetitive self-grooming and jumping, as was hoped based on past studies with similar compounds. More importantly, perhaps, GRN-529 also improved some aspects of sociability – a welcome surprise as this benefit had not been seen previously with such compounds.

“It is remarkable to consider the possibility that one pharmacological target could be beneficial for two of the three diagnostic symptoms of autism,” says study co-author Jacqueline Crawley, Ph.D., chief of the Laboratory of Behavioral Neuroscience at the National Institute of Mental Health. “We emphasize caution in over-interpreting our early findings, because mouse models have limitations as well as strengths. The next several years will reveal the usefulness in alleviating symptoms of autism.” Indeed, many experimental medicines that show early promise in animal models fail to do so in humans for a variety of reasons.

“It will be critical to test GRN-529 and [related] compounds in other models of autism spectrum disorders,” adds Pfizer co-author Daniel Smith, Ph.D. “A better understanding of autism biology may help identify specific patient populations that would benefit from this and other types of therapies.”

Autism Speaks is currently funding other research studies involving glutamate. You can explore these and other research using our Grant Search.

Reported by Autism Speaks science writer Laurie Tarkan