Modulation of cAMP and ras signaling pathways improves distinct behavioral deficits in a zebrafish model of neurofibromatosis type 1

Cell Rep. 2014 Sep 11;8(5):1265-70. doi: 10.1016/j.celrep.2014.07.054. Epub 2014 Aug 28.


Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder associated with attention deficits and learning disabilities. The primary known function of neurofibromin, encoded by the NF1 gene, is to downregulate Ras activity. We show that nf1-deficient zebrafish exhibit learning and memory deficits and that acute pharmacological inhibition of downstream targets of Ras (MAPK and PI3K) restores memory consolidation and recall but not learning. Conversely, acute pharmacological enhancement of cAMP signaling restores learning but not memory. Our data provide compelling evidence that neurofibromin regulates learning and memory by distinct molecular pathways in vertebrates and that deficits produced by genetic loss of function are reversible. These findings support the investigation of cAMP signaling enhancers as a companion therapy to Ras inhibition in the treatment of cognitive dysfunction in NF1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cyclic AMP / metabolism*
  • Learning*
  • MAP Kinase Signaling System
  • Memory*
  • Neurofibromatosis 1 / metabolism*
  • Neurofibromatosis 1 / physiopathology
  • Neurofibromin 1 / genetics
  • Neurofibromin 1 / metabolism*
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*
  • ras Proteins / metabolism*


  • Neurofibromin 1
  • Zebrafish Proteins
  • Cyclic AMP
  • ras Proteins