Modulation of cAMP and Ras Signaling Pathways Improves Distinct Behavioral Deficits in a Zebrafish Model of Neurofibromatosis Type 1

Marc A. Wolman, Eric D. deGroh, Sean M. McBride, Thomas A. Jongens, Michael Granato, Jonathan A. Epstein

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

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 ofdownstream targets of Ras (MAPK and PI3K) restores memory consolidation and recall but notlearning. 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.

Original languageEnglish (US)
Pages (from-to)1265-1270
Number of pages6
JournalCell Reports
Volume8
Issue number5
DOIs
StatePublished - 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology

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