UCLA scientists have discovered the brain mechanism that causes learning disabilities in neurofibromatosis 1 (NF1), an inherited disease marked by disfiguring tumors. Reported in the Jan. 16 online edition of Nature, the discovery will lead to new treatments for the disease, which affects nearly one million people worldwide.

"Our study provides the first clear picture of what disrupts learning in NF1," explained Dr. Alcino J. Silva, principal investigator and UCLA professor of neurobiology, psychiatry and psychology. "More importantly, our findings demonstrate how to successfully reverse these learning problems in the brain."

NF1 afflicts one out of 4,000 people in the world. The genetic disorder usually surfaces in childhood, when youngsters develop learning disabilities and behavioral problems often mistaken for Attention Deficit Disorder. The disorder's trademark cafe-au-lait spots and disfiguring tumors appear under the skin in the late teens and early adulthood. Surgeons sometimes can remove the tumors if the lesions have not grown around key nerves.

Silva and his colleagues studied an animal model using mice bred with the genetic mutation for NF1. In earlier research, Silva's team demonstrated that NF1 mice couldn't follow visual cues and swim their way through a water maze as easily as normal mice. The results pointed to a problem with the hippocampus -- the part of the brain where spatial learning and memory take place.

Zeroing in on the hippocampus, the researchers traced the origin of NF1's learning problems to a protein called Ras, which transmits signals in cells. Normally, the NF1 gene switches off this protein. But Silva's team discovered that mice with the NF1 mutation possessed considerably less NF1 in the brain. As a result, Ras continued firing signals to the cells at a hyperactive rate, interfering with the learning process.

"Our brain cells need a precise amount of Ras activity to perform properly," explained Silva. "It's a delicate balance. Too much or too little will disrupt learning, resulting in a veritable traffic jam of cellular communication."

To confirm these findings, Silva's colleagues Rui Costa and Nikolai Fedorov measured the electric signals between brain cells and found them dramatically impaired in the mice with the NF1 mutation. As a result, these mice took longer to learn and remember each task than normal mice.

"Synaptic changes form the basis for learning in the brain," Silva said. "When we connected the disorder to this process, we knew we'd found the brain mechanism responsible for NF1's learning problems. More importantly, now that we knew the mechanism at fault - we could try to reverse it."

The UCLA team reasoned that they could improve the NF1 mice's learning if they corrected their chemical imbalances. The researchers decreased the amount of Ras in the animals' brains by administering an experimental drug and genetically altering Ras at birth.

"We were delighted to see that both methods successfully reduced the amount of Ras in the brain and cured the mice's learning problems," said Silva. "The NF1 mice performed spatial learning tasks as easily as the normal mice."

According to Silva, NF1 studies offer insight into understanding other learning disabilities, which affect an estimated 35 million Americans. Unveiling the causes of NF1-related learning problems will bring scientists closer to comprehending other learning disabilities.

"Scientists finally have the first positive news about NF1 learning disabilities for patients and their families," said Silva. "We hope that our findings will translate into real help for them."

The experimental drug that Silva's team used to reverse the NF1 mice's learning disorders is currently undergoing clinical trials to cure NF1-related tumors. Silva noted that a single treatment to simultaneously cure both symptoms might become a reality in the future.

The UCLA study was supported by the National Institute of Neurological Disorders and Stroke; National Neurofibromatosis Foundation; Neurofibromatosis, Inc; and a private donation by Ms. Carol Moss Spivak.
 

---UCLA

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