Scientists have discovered that they can improve memory and reduce repetitive behavior in animal models of Fragile X syndrome by adjusting the levels of a signaling protein called PIKE. The researchers' findings in mice and fruit flies, published May 5th in Cell Reports, suggest that PIKE signaling is critically involved in the neuronal and behavioral defects caused by Fragile X, which is the most common inherited cause of intellectual disability. Understanding how the developmental disorder skews nerve-cell signaling gives researchers a better foundation for developing effective treatments.

Fragile X syndrome is caused by a mutation in a gene called FMR1. Because of this mutation, production of many proteins, including PIKE, is elevated. Misregulation of PIKE has been implicated in a number of brain disorders, and there is evidence that the protein is overactive in the brains of people with Fragile X.

Gary Bassell, Ph.D., at Emory University School of Medicine, recipient of NARSAD 2009 Independent Investigator and 2012 Distinguished Investigator grants, led a team of researchers. The scientists suspected that overactive PIKE might contribute to excessive signaling by a class of cellular receptors for the neurotransmitter glutamate. This defect impairs neuronal function in people with Fragile X. Drugs that aim to treat Fragile X syndrome by targeting glutamate receptors directly have shown disappointing results in recent clinical trials, underscoring the need for alternative treatment strategies.

Dr. Bassell's team also included Christina Gross, Ph.D, a 2013 Young Investigator grantee and Eric Klann, Ph.D., a 2013 Distinguished Investigator grantee. The researchers used genetic tools to reduce the levels of PIKE in mice and fruit flies genetically engineered to mimic Fragile X syndrome. In both animal models, reducing PIKE eliminated molecular and cellular defects linked with Fragile X. What's more, the scientists found that the genetic manipulation of PIKE altered the animals' behavior.

In the mouse model of Fragile X, animals exhibit repetitive, autistic-like behaviors. The researchers found that reducing PIKE in these animals reduced repetitive behavior and enabled the mice to build their nests more efficiently. In the team's experiments using fruit flies with Fragile X-like deficiencies, reducing PIKE restored short-term memory.

The findings offer insight into how the genetic mutation that causes Fragile X syndrome alters signaling in nerve cells, interfering with their ability to adapt to changes in signaling from neighboring cells.

Read the abstract.