Studies on learning disabilities associated with neurofibromatosis type 1, or NF1, indicate the problem to excessive activity of a crucial signaling molecule and have successfully reversed the disabilities in mice by giving them an experimental drug. The findings provide hope that these learning problems may one day be treatable in humans.

NF1 is a genetic disorder that affects about one in every 4000 people. Patients with the disorder have an array of symptoms, including benign tumors called neurofibromas and light brown spots on the skin called café-au-lait spots. About half of the affected individuals have cognitive disabilities, which typically include problems with spatial learning (which affects organization and other abilities) and reading.

In the new study, Dr. Silva, Rui M. Costa, and colleagues studied mice with a mutation in the gene for NF1. This gene produces a protein called neurofibromin that controls activity of a signaling protein called Ras. To investigate whether Ras plays a role in NF1-associated learning impairments, the researchers crossed the NF1 mice with mice that had another mutation (K-ras) that decreases Ras activity. They found that mice with mutations in either NF1 or K-ras had impaired performance on a test of spatial learning called the water maze test. Mice with both mutations, however, did as well as normal mice on this test. This suggests that the learning impairment in the NF1 mice was due to an excessive amount of Ras signalling and that this impairment can be surmounted by reducing the amount of Ras. The scientists also found that they could improve learning in the NF1 mice using an experimental drug that prevents Ras from carrying out its signaling role in cells.

The researchers also found evidence that explains how the abnormal NF1 gene leads to learning disabilities. Neurofibromin normally controls Ras activity and keeps it in check. Without this control, too much Ras signalling occurs. Experiments showed that the abnormal Ras activity increases nerve signals that inhibit activity-related changes (plasticity) in the synapses between neurons. Researchers believe these synaptic changes, called long- term potentiation or LTP, are the basis for learning in the brain.

The finding that drug therapy could reverse the learning impairment in adult mice is important because many scientists and physicians have thought that NF1-related learning problems are due to abnormal brain development, says Dr. Silva. The new study suggests that this may not be the case and provides hope for treating the thousands of NF1 patients worldwide who experience learning problems.The drug that reversed the NF1-associated learning impairments in mice is already in clinical trials to determine if it can help reduce the number of tumors in NF1, Dr. Silva says.

The researchers were surprised to find that the K-ras mutants, which have too little Ras signaling, had learning impairments just like the NF1 mutants, which have too much Ras, says Dr. Silva. This finding suggests that a specific amount of Ras activity -- not too much and not too little - is important for learning.

This study is one of the first instances in which researchers have been able to reduce the symptoms of a neurological disorder in an animal model using their understanding of the molecular interactions that cause the disorder, says Dr. Silva.

While these findings are encouraging, the researchers caution that they are not the entire story. Scientists need to confirm these findings and determine what cell types play a role in these learning impairments.