Date of Award
Doctor of Philosophy (PhD)
Thomas A. Jongens
Autism is a neurodevelopmental condition that is highly heterogeneous in its clinical presentation. In addition to differences in social interaction and communication, and the presence of restrictive, repetitive behaviors, metabolic dysfunction is becoming more widely known and studied as a co-occurring condition seen in autistic individuals. However, the etiology of these metabolic alterations in autism remains unclear. Here, we utilized a combination of metabolomic, physiological, and behavioral assays to investigate how disruption of the autism-risk gene, neurexin-1, influences energy metabolism and associated behaviors in Drosophila melanogaster. These analyses revealed that Drosophila lacking neurexin-1 expression exhibit decreased resistance to environmental stressors, specifically starvation stress and heat stress. These findings lead us to consider whether the neurexin-1 mutant flies have an altered metabolic status, thus we performed metabolomics and complementary colorimetric assays and found that these flies have a distinct metabolic profile, with decreased lipid and carbohydrate stores. Moreover, neurexin-1-null Drosophila exhibit decreased levels of NAD+, an important cofactor in many energy production pathways. Interestingly, loss of neurexin-1 also results in disruptions in mitochondrial morphology in Drosophila flight muscle, in addition to decreased flight ability. Finally, we observed mechanically-induced seizure-like activity in the neurexin-1 mutant flies, which closely mimics clinical data wherein patients with deletions in Neurexin-1 experience seizures. Together, these findings point to a novel role for neurexin-1 in the regulation of energy metabolism and autism-related behavioral phenotypes in Drosophila, in addition to providing a foundation for further investigation into the etiology of metabolic dysfunction and seizures in autism.
Levy, Kyra Alexandra, "Investigation Of Metabolism And Autism-Relevant Behaviors In Drosophila Lacking Neurexin-1" (2022). Publicly Accessible Penn Dissertations. 4708.