Tom Jongens, Ph.D., Principal Investigator
University of Pennsylvania
Sean McBride, Graduate Student
Albert Einstein College of Medicine
Catherine Choi, Graduate Student
Drexel University

FRAXA Awards:
  $70,000 in 2004
  $35,000 in 2003
  $35,000 in 2002

Fragile X is featured in Newsweek magazine. It discusses Tom Jongens' finding which suggests that compounds which dampen the mGluR receptor could treat Fragile X.

Genetics: A 'Striking' Fragile X Finding? Newsweek - USA

(Press Release from University of Pennsylvania School of Medicine)

Fragile X Syndrome is one of the most commonly inherited forms of mental retardation, with an incidence of 1 in 4,000 males and 1 in 8,000 females. Not many medications exist to help Fragile X patients. Now, in a fruit fly model of the disease, researchers from the University of Pennsylvania School of Medicine and their colleagues have shown that it is possible to reverse some of the symptoms of the disorder using drugs that dampen specific neuronal overactivity. Their findings appear in the March 3, 2005 issue of Neuron.

Characteristics of Fragile X in people include an average IQ of about 50, deficits in certain types of short-term memory, autistic behavior, sleep problems, hyperactivity, attention deficits, and susceptibility to seizures. In humans, Fragile X syndrome is caused by the FMR1 gene not working properly or at all. This gene encodes the FMRP protein, which controls the availability of select proteins involved in neuron-to-neuron communication.

Senior author Thomas A. Jongens, PhD, Associate Professor of Genetics at Penn, and colleagues from Albert Einstein College of Medicine and Drexel University College of Medicine, as well as other labs, have developed and characterized a Drosophila fly model for Fragile X. This model is based on mutants that lack the dfmr1 gene, which encodes a protein similar to human FMR1 protein. "Interestingly, work by my lab and others have found that the dfmr1 mutants display many physical and behavioral characteristics similar to symptoms displayed by Fragile X patients," says Jongens. These include structural defects in certain neurons, enlarged testes, failure to maintain proper day/night activity patterns; attention deficits and hyperactivity, and defects in behavior-dependent learning and memory.

"Our thinking was that since so many of the behavioral and physical phenotypes in the fly model were similar to symptoms observed in fragile X patients and a mouse fragile X model, FMR1 and dfmr1 must be regulating similar biological processes in human, mice, and flies," states Jongens.

A mouse model of Fragile X also shows symptoms similar to those of Fragile X patients. Studies outside of Penn using the mouse model have demonstrated that Fragile X patients have a tendency to break down synaptic connections (sites used for neuron to neuron communication) more readily than the general population. This breakdown is due to an increased activity in the metabotropic glutamate receptor (mGluR), which is located on the surface of neurons, including in the hippocampus -- the memory and learning center in the brain. In turn, this increased activity compromises neurotransmission for memory-associated functions.

Jongens and colleagues surmised that mGluR overactivity may be at the root of many of the Fragile X symptoms. Using such drugs as lithium chloride and others, known as antagonists, that block mGluR's activity, the team tested to see if the drugs could rescue any of the observed behavioral and memory defects observed in the fly model.

"What we found was very striking," says Jongens. They found that the drug treatments restored memory-dependent courtship behavior in mutant flies and reversed some of the neuronal structural defects. The group used lithium because it is known to have activities analogous to blocking mGluR-receptor activity, and it is already an FDA-approved drug used to treat other ailments in humans such as bipolar disorder.

"The big take-home message from our work is that maintaining proper regulation of mGluR signaling is a conserved function of the dFMR1 and FMRP proteins and that loss of dfmr1 function in flies leads to at least a subset of the cognitive and behavioral defects observed in the fly model," says Jongens. "These results provide a potential route by which symptoms of Fragile X patients may be ameliorated."

First authors on the paper are Sean M.J. McBride, Albert Einstein College of Medicine, and Catherine H. Choi, Drexel University College of Medicine. This work was funded by the National Institutes of Health and the FRAXA Research Foundation, Newburyport, MA.

by Tom Jongens, 3/2004

The Drosophila (fruit fly) genome contains a single gene, called dfmr1, that is similar to the human FMR1 gene. In flies, loss of dfmr1 function leads to behavioral and neuronal defects similar to symptoms observed in Fragile X patients. One behavioral defect displayed by Fragile X flies is the loss of normal circadian rhythms. A normal fly is active for 12-14 hours during daylight and relatively inactive for 10-12 hours at night. If entrained to a light:dark cycle of 12 hours of light followed by 12 hours of dark for several days, a normal fly can maintain a normal pattern of activity in total darkness for up to 3 weeks. But dfmr1 mutant flies lack this capacity and display an erratic pattern of activity. Similarly, some children with Fragile X have great difficulty sleeping through the night.

Another behavioral change in Fragile X flies is a failure to display immediate recall in a courtship-based learning and memory assay. When placed in a small chamber with an unreceptive female (a previously mated female), normal males learn that their courtship attempts will not be successful and they drastically reduce their attempts. This learning occurs within one hour. These "trained" males remember this negative experience over the next several hours and so they do not court when placed in a new chamber with a receptive (unmated) female. Interestingly, we have observed that the dfmr1 mutant males learn during the one-hour "training" session with the unreceptive female, but fail to display any memory of this experience, even if they are immediately placed in a new chamber with a receptive female.

In collaboration with Sean McBride and Tom McDonald at Albert Einstein College of Medicine, we are attempting to identify drugs that ameliorate the two defects described above. Since these studies and others suggest that there is a defect in synaptic plasticity in all Fragile X models, we will test the effect of drugs that are known to alter the activity of neuronal receptors that modulate synaptic plasticity.

Already we have tested mGluR antagonists (MPEP and other compounds) and have seen some very promising rescue of the defects observed in the courtship based learning and memory assay, including rescue of short-term memory.