In 1995 Yi Zhong showed that the ras pathway was a mediating factor in the transmission of certain (G-protein-coupled) neurological impulses. In 1996, Yi's studies moved toward the investigation of the relationship between ras and the Neurofibromatosis type I (NF1) tumor suppressor gene. NF1 is one of the most commonly inherited neurological disorders in humans. The disease is characterized by tumors (frequently benign), developmental abnormalities, including reduced height, and in many patients (30-45%) specific learning disabilities.

The activity of ras determines the response of cells to a number of signals, including growth factors, that mediate cell proliferation, growth, and differentiation. ras activity can be inhibited by a number of proteins including NF1. Since it is known that elevated ras activity causes cancer in many human tissues, the diminished inhibition of ras activity in NF patients may well contribute to the development of NF symptoms. However, the story has become even more interesting as Yi Zhong has discovered that the NF1 protein also controls another biochemical pathway in addition to inhibiting the activity of ras. Yi's lab obtained mutant Drosophila that lacked the NF1 gene from Andre Bernards at the Massachusetts General Hospital in Boston and uncovered a link between NF1 and the cyclic AMP signaling pathway. The latter pathway was previously shown by Tim Tully and Jerry Yin of CSH and others to control learning and memory in Drosophila. Yi found that the NF1 defect could be eliminated by providing small molecules that could activate the cyclic AMP pathway. These results suggest these small molecules as candidate drugs for treatment of NF.

Alcino Silva, who has done important work with mice, has uncovered a mouse model for the study of learning and memory deficits associated with NF. He obtained a line of NF1+/--mice (one good copy of the gene and one defective) from Tyler Jacks, a collaborator at MIT, and demonstrated learning difficulties similar to those in human NF patients. The development of a mammalian model for the NF disease is facilitating extensive studies of NF that would not be possible in human subjects. These mice will also be valuable in assessing the effects of drugs that affect the cyclic AMP pathway. I am particularly pleased that these exciting results on NF come so soon after the watershed meeting on NF research held at the Banbury Conference Center in late 1995.

In another research project, Alcino continues to study the role of the CREB protein, a target of cyclic AMP, in learning and memory in mice. This year, he had the very exciting success of achieving behavioral rescue in CREB mutant, learning-impaired mice. He demonstrated conclusively that by modifying training regimens for the CREB mutants he was able to overcome profound long-term memory deficits. In these studies Alcino altered the number of training sessions and the length of the rest interval between them. This work follows from the elegant studies on the role of CREB in learning and memory by Tim Tully and Jerry Yin. These examples of successful behavioral rescue through modified training have tremendous implications for the treatment of memory disorders.