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

Abstract

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.

In Vivo Ca2+ Imaging Reveals that Decreased Dendritic Excitability Drives Startle Habituation

“…Habituation of response probability and magnitude in C. elegans following tap stimulation have been demonstrated to rely on different mechanisms (Kindt et al, 2007), and so it will be interesting to test whether this holds true for habituation of other larval zebrafish behaviors that exhibit graded responses such as the O-bend response to changes in illumination (Wolman et al, 2014). The optical method we describe here provides a powerful, non-invasive technique for investigating changes in circuit activity in an intact, genetically tractable vertebrate organism during learning.…”

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

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The NF1 gene in tumor syndromes and melanoma

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