Using a zebrafish model of a human genetic disease called neurofibromatosis (NF1), a team from the Perelman School of Medicine at the University of Pennsylvania (Penn) has found that the learning and memory components of the disorder are distinct features that will likely need different treatment approaches. The research results were published in the September 11, 2014 issue of Cell Reports. NF1 is one of the most common inherited neurological disorders, affecting approximately one in 3,000 people. It is characterized by tumors, attention deficits, and learning problems. Most people with NF1 have symptoms before the age of 10. Therapies target Ras, a protein family that guides cell proliferation. The NF1 gene encodes neurofibromin, a very large protein with a small domain involved in Ras regulation. Unexpectedly, the Penn team showed that some of the behavioral defects in mutant fish are not related to abnormal Ras, but can be corrected by drugs that affect another signaling pathway controlled by the small molecule cAMP. They used the zebrafish model of NF1 to show that memory defects – such as the recall of a learned task -- can be corrected by drugs that target Ras, while learning deficits are corrected by modulation of the cAMP pathway. Overall, the team's results have implications for potential therapies in people with NF1. "We now know that learning and memory defects in NF1 are distinct and potentially amenable to drug therapy," says co-senior author Jon Epstein, M.D., Chair of the Department of Cell and Developmental Biology. "Our data convincingly show that memory defects in mutant fish are due to abnormal Ras activity, but learning defects are completely unaffected by modulation of these pathways.
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