Developmental loss of neurofibromin across distributed neuronal circuits drives excessive grooming inDrosophila

Abstract

Author summary Neurofibromatosis type 1 results in increased susceptibility to cognitive and behavioral symptoms, such as attention-deficit/hyperactivity disorder. This suggests that the underlying genetic mutations affect neuronal function. Where and when these effects occur in the brain is not understood. We approached these questions in the genetically-powerful fly model, examining how loss of theNF1gene affects a complex motor behavior, grooming. Loss ofNF1during brain development caused excessive grooming in adult animals. This suggests that the gene plays a key role in brain development, which may be important for treatment of the disorder. Further, we found that a specific signaling pathway, Ras, is involved in regulating this grooming behavior. Finally, we mapped where in the brainNF1is required to maintain normal levels of grooming. The data suggested that it is required across many neurons, rather than in small subsets. When NF1 was knocked down in smaller subsets, there was no effect, but if two subsets were added together, an effect was produced. This means that NF1 regulates the function of many neurons and brain regions to influence complex behaviors. Neurofibromatosis type 1 is a monogenetic disorder that predisposes individuals to tumor formation and cognitive and behavioral symptoms. The neuronal circuitry and developmental events underlying these neurological symptoms are unknown. To better understand how mutations of the underlying gene (NF1) drive behavioral alterations, we have examined grooming in theDrosophilaneurofibromatosis 1 model. Mutations of the flyNF1ortholog drive excessive grooming, and increased grooming was observed in adults whenNf1was knocked down during development. Furthermore, intactNf1Ras GAP-related domain signaling was required to maintain normal grooming. The requirement forNf1was distributed across neuronal circuits, which were additive when targeted in parallel, rather than mapping to discrete microcircuits. Overall, these data suggest that broadly-distributed alterations in neuronal function during development, requiring intact Ras signaling, drive keyNf1-mediated behavioral alterations. Thus, global developmental alterations in brain circuits/systems function may contribute to behavioral phenotypes in neurofibromatosis type 1.