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

•nf1-deficient zebrafish exhibit significant learning and memory deficits•Acute treatment with Ras pathway antagonists restores memory but not learning•Acute treatment with cAMP pathway agonists restores learning but not memory•Modulation of both cAMP and Ras signaling may benefit cognitive dysfunction in NF1

SummaryNeurofibromatosis 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.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slide