Inhibition of Cxcr4 chemokine receptor signaling improves habituation learning and increases cAMP-PKA signaling in a zebrafish model of Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder caused by loss of function mutations in the gene neurofibromin 1 (NF1). NF1 encodes neurofibromin, a multifunctional tumor suppressing protein that regulates Ras, cAMP, and dopamine signaling. NF1 predisposes patients to a wide range of symptoms, including peripheral nerve tumors, brain tumors, and cognitive dysfunction. Despite considerable work using animal models to investigate the role of neurofibromin in behavior, translating research into treatment for NF1-associated cognitive dysfunction has not yet been successful. Here, we identify Cxcr4 chemokine receptor signaling as a regulator of habituation learning and modulator of cAMP-PKA signaling in nf1 mutant larval zebrafish. Combining a small-molecule drug screen and RNAseq analysis, we show that cxcr4b expression is increased in nf1 mutants and that pharmacological inhibition of Cxcr4 with AMD3100 (Plerixafor) improves habituation learning in nf1 mutants. We further demonstrate that Plerixafor treatment activates cAMP-PKA pathway signaling but has limited effects on Ras-Raf-MEK-ERK pathway signaling in the nf1 mutant brain. CXCR4 was previously identified as a potential therapeutic target for neurofibromin-deficient tumorigenesis. Our results provide evidence that Cxcr4 signaling also regulates neurofibromin-dependent cognitive function.