Molecular and Neural Mechanisms of Social Behavioral Differences in NF1
Abstract
Purpose: Compared to children in the general population, children with loss-of function mutations in the Neurofibromatosis type 1 (NF1) gene have greatly increased rates of autism spectrum disorder (ASD). Social and communicative disabilities in NF1 patients are among the greatest contributors to disease morbidity. Yet, the mechanisms by which loss of NF1 results in ASD and social deficits remain largely unknown, and no treatments effectively address these pervasive issues. Lack of progress in this area derives in part from a paucity of experimentally tractable animal models of social deficits in NF1. The Drosophila melanogaster model of NF1 recapitulates many features of the human disease; insights from the fly have led to important advances in NF1 biology and therapeutics. We find that Drosophila NF1 mutants display prominent impairments in social behaviors. We are poised to use this model towards a mechanistic understanding of how social deficits arise in NF1, and to define new treatment targets. Scope: Our data demonstrate that social impairments in NF1 mutant flies arise from a specific defect in peripheral sensory processing. The proposed studies will build on these data to establish the role of Nf1 in sensory gating within behaviorally relevant neural circuits. Experiments aim to determine the mechanism through which loss of Nf1 impairs sensory neuron function, define how impaired sensation translates to altered brain activity and disrupted behavioral output, and identify small molecules targets that can restore normal behavioral output. Major findings: We have made major progress towards each aim of the proposed work. This includes development of machine-learning approaches for automated behavioral annotation of social behaviors in flies, which will greatly accelerate all proposed aims. Recent findings implicate specific ion channels acting downstream of Nf1 to effect sensory neuron excitability.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1193688
Entities
People
- Matthew S Kayser
Organizations
- University of Pennsylvania