Zebrafish <i>neurofibromatosis type 1</i> mutants show disruption of sleep but not of circadian rhythms

Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder that is associated with several developmental and behavioral phenotypes, including reduced and fragmented sleep at night. Here, we describe the role of NF1 in sleep in zebrafish, a diurnal vertebrate whose mechanisms of sleep control are broadly conserved with those of mammals. The zebrafish genome encodes two neurofibromin 1 (nf1) paralogs: nf1a and nf1b, which function in a partially redundant manner. We found that zebrafish with reduced nf1 function exhibit decreased and delayed sleep at night, similar to humans with the NF1 disorder, in a dose-dependent manner. Zebrafish nf1 mutants also exhibit shorter sleep bouts, decreased arousal threshold, and decreased sleep depth, consistent with disrupted sleep, and show increased sleep in the morning. Finally, we found that zebrafish nf1 mutants have intact behavioral circadian rhythms, and the nf1 mutant sleep phenotype does not require entrained circadian rhythms. These results establish a vertebrate nf1 model that recapitulates key aspects of human NF1-associated sleep disturbances and provides a basis to explore mechanisms through which NF1 regulates sleep. This study also suggests that disrupted sleep in the human NF1 disorder is directly due to reduced NF1 function, rather than a secondary symptom of the disorder.