Austin 5HT Candidate Gene Discovery with C Elegans

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DESCRIPTION (provided by applicant): Autistic spectrum disorders are a group of behavioraily-defined developmental disorders that all share core deficits, however, the pathophysiology of these disorders is undefined. Evidence suggests a multigenic etiology, but the underlying genes and biochemical pathways they subserve remain unknown. Hyperserotonemia is the most consistent biochemical feature observed, however the PI has recently published on an apparently distinct new biochemical phenotype, subtle deficiencies in mitochondrial energy metabolism (ME), first discovered in special subsets of children with autism. The Gargus and Sze labs recently moved adjacent to one another in the new Sprague Hall. The Sze lab had been carrying out genetic and behavioral studies of the serotonin (5HT) signaling pathway in a model organism, C elegans, an organism ideally suited to the discovery of novel gene targets in the pathway, and screening for novel therapeutics that alter it, since it has a completely defined genome and nervous system and only nine 5HT neurons. The Sze lab had carried out pioneering studies demonstrating the role of 5HT in ME and developmental arrest of the worm, remarkably, phenotypes "sounding" like those being discussed in autism by the Gargus lab. 5HT-deficient worms have altered dauer arrest, fat metabolism and altered DAF2 insulin/IGF receptor signaling to the DAF16/ FOXO transcription factor, a pathway known to modulate the expression of genes involved in ME. Synergy between the two groups, and excitement that unexpected genetic unification of disparate phenotypes in 5HT, ME and developmental regulation might be seen through the window of this signaling pathway in this powerful animal model system, underlie this proposal. To seed this new translational collaboration and to test the hypothesis that discoveries in C elegans 5HT signaling will lead to compelling new functional candidate genes to be tested in association studies in autism, potentially leading to novel diagnostics and therapeutics, we specifically propose three primary objectives: 1) Directly assessing ME and developmental arrest in 5HT-deficient C elegans 2) Using this system to isolate worm mutants resistant to the serotonergic drugs used in the treatment of autism (SSRIs, 5HT receptor blockers and tricyclics) to define and isolate novel genes in this pathway 3) Identification and resequencing of human homolog candidate genes to prototype assays for future collaborative studies in autistic cohorts.