Molecular and Neural Mechanisms of Social Behavioral Differences in NF1
Abstract
Neurofibromatosis type 1 (NF1) is a debilitating neurodevelopmental disorder characterized primarily by tumors of the nervous system. In addition, cognitive disabilities and autistic features are highly prevalent. Indeed, up to 50% of patients have learning disabilities, with similar rates of autism spectrum disorder. Moreover, social behavioral deficits are a primary manifestation of the autistic disorder, with patients exhibiting impaired social information processing, social communication, and social interactions. However, no treatments for NF1 effectively address social behavioral deficits, which contribute greatly to disease morbidity. NF1 is caused by mutations in the neurofibromin 1 gene resulting loss of function of the protein product. Neurofibromin 1 normally serves as a key regulator of another protein, Ras. Without neurofibromin to regulate Ras in NF1 patients, cells divide in an uncontrolled manner, leading to tumors. In contrast to the tumorigenic symptoms of NF1, little is known about the molecular and cellular basis of social behavioral differences, limiting the design of novel treatment strategies. The short- and long-term goals of this research proposal are to determine the mechanisms by which neurofibromin 1 regulates social function and to identify new drugs to antagonize social deficits in an NF1 animal model. Animal models of NF1, especially the fruit fly, Drosophila melanogaster, have improved understanding of tumor formation and cognitive dysfunction and led to new treatments for these symptoms. However, no animal model has been developed to study neurobiological processes causing social behavioral dysfunction in NF1. We have found in a Drosophila model of NF1 that mutant males display impairments in social behaviors. Surprisingly, we discovered that these social impairments arise from a previously unknown function for neurofibromin in a group of peripheral sensory neurons. These data raise the exciting possibility that disrupted flow of sensory information from the periphery to the brain, rather than a primary deficit in the brain, gives rise to social deficits in NF1. The more accessible peripheral sensory system could then be a target for therapeutic intervention, with transformative potential for patients. The scientific objectives of the proposed work are to (1) determine the mechanism through which loss of Nf1 impairs sensory processing; (2) define how impaired sensation translates to altered brain activity and disrupted behavior; and (3) conduct a high-throughput drug screen in live animals to identify novel compounds that can restore normal social behavioral output. Drosophila is an ideal model in which to carry out the proposed line of work for both technical feasibility and the genetic accessibility of its precisely mapped neural circuitry. Moreover, Drosophila-based discovery paths have been successful in other neurodevelopmental diseases and thus are likely over the long-term to be highly relevant to humans. A deeper understanding of the specific defect we have discovered will set the stage for bench-to-bedside translation. Results from this work have potential to benefit NF1 patients with comorbid autism spectrum disorder by providing basic insights into how autistic features arise and thereby guiding the field to focus on sensory processing. In addition, we anticipate identifying new drug targets that might be directly applicable to the human disorder. Sensory processing is a readily testable entry-point into social behavioral dysfunction, so findings from these experiments have a high potential to rapidly impact the clinical setting.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010206
Entities
People
- Matthew S Kayser
Organizations
- United States Army
- University of Pennsylvania