Investigation of the Function of ASD-Associated Gene Neurexin in Drosophila and C. Elegans

Poster Presentation
Friday, May 3, 2019: 11:30 AM-1:30 PM
Room: 710 (Palais des congres de Montreal)
K. A. Levy1, M. P. Hart2, E. D. Weisz2, Z. Zhou2, E. S. Brodkin3, M. Bucan2 and T. A. Jongens2, (1)Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, (2)Department of Genetics, University of Pennsylvania, Philadelphia, PA, (3)Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
Background: Mutations in a gene encoding a synaptic cell adhesion molecule, NEUREXIN1 (NRXN1), are significantly enriched in individuals with Autism spectrum disorder (ASD), indicating that NRXN1 may play a role in the pathophysiology of ASD, albeit through an unknown mechanism. In mammals, there are three NRXN genes (NRXN1-3), each of which has two promoters for two main isoforms: α-NRXN (long isoform) and β-NRXN (short isoform). NRXN1 is also subject to extensive alternative splicing, resulting in potentially thousands of variants. Invertebrates such as Drosophila melanogaster and Caenorhabditis elegans have only one neurexin-1 gene that encodes a protein that is structurally similar to α-NRXN in vertebrates. Therefore, Drosophila and C. elegans serve as useful systems to study NRXN1 involvement in ASD due to the reduced complexity and highly conserved nature of neurexin-1.

Objectives: The goals of our current studies are to identify conserved ASD-related behavioral phenotypes, such as sleep and stress responses, in both flies and worms and to determine the underlying mechanism(s) by which neurexin may regulate these behaviors.

Methods: To monitor sleep and activity we utilize the Drosophila Activity Monitoring system (DAM) and the WorMotel for Drosophila and C. elegans, respectively. For starvation stress experiments, the same activity monitoring systems are used except animals are given only water.

Results: To date, we have observed conserved defects in sleep and in behavioral responses to starvation stress. We find that neurexin-null mutants show decreased activity and fragmented sleep when compared to control animals. Fragmented sleep in neurexin-null Drosophila has been shown previously (Larkin et al., 2015; Tong et al., 2016), and thus our findings confirm these results and reveal that this is a conserved defect across species in both flies and worms. Additionally, we have identified decreased responding to starvation stress in neurexin-null Drosophila and C. elegans. When put under starvation conditions both Drosophila and C. elegans become hyperactive, with Drosophila also suppressing their sleep, which is thought to promote acquisition of food. Neurexin-null flies and worms however, show abnormalities in this stress response, wherein they display delayed, decreased hyperactivity and a failure to suppress sleep during starvation.

Conclusions: Our findings show that neurexin-null flies and worms show conserved deficits in sleep and stress response behaviors, both of which can be affected in individuals with ASD. Future studies will investigate the spatial and temporal sufficiency of neurexin in promoting sleep and starvation-stress response behavior using genetic techniques to restore neurexin expression in specific neuronal subsets during adulthood. These studies will have an impact on how we think about the ability of treating individuals with NRXN1 mutations after early developmental periods have ended. Additionally, we would like to investigate how neurexin may regulate octopamine, which is a neurotransmitter that has been shown to be required for starvation hyperactivity. By using two model organisms we have the unique ability to study neurexin functioning in simpler neural systems, and our consistent phenotypic observations between both systems provide confidence that the mechanisms by which neurexin functions to promote ASD-related behaviors are conserved across species.

See more of: Animal Models
See more of: Animal Models