Researchers Identify Potential Treatment For Learning Disability In Neurofibromatosis

This study provides the first clear picture of what causes learning impairments in NF1, says study author Alcino J. Silva, Ph.D., of the University of California, Los Angeles (UCLA). 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. The study appears in the January 16, 2002, electronic edition of Nature* and was supported in part by the National Institute of Neurological Disorders and Stroke (NINDS).

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 signaling 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 signaling 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 sugges