Habituation in high-throughput genetic model organisms as a tool to investigate the mechanisms of neurodevelopmental disorders

• Published in: Neurobiology of learning and memory Vol. 171; p. 107208
• Main Authors: Kepler, Lexis D., McDiarmid, Troy A., Rankin, Catharine H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2020
• Subjects: Drug screens; Habituation; High-throughput model organisms; Humanization; Neurodevelopmental disorders; Variants of unknown significance; Variants of unknown significance; Neurodevelopmental disorders; Humanization; High-throughput model organisms; Habituation; Drug screens
• ISSN: 1074-7427; 1095-9564
• DOI: 10.1016/j.nlm.2020.107208

•Habituation impairments are present in multiple neurodevelopmental disorders.•Habituation and many risk genes are conserved in high-throughput model organisms.•Assessing habituation can determine the pathogenicity of risk genes and variants.•Habituation can be used to identify molecular pathways and therapeutic targets.•Entire candidate gene lists can be assessed quickly using machine vision trackers.
Alterations in habituation, a highly conserved form of non-associative learning, are suspected to contribute to a range of the complex behavioural phenotypes present in multiple neurodevelopmental disorders. While progress has been made in understanding the genetics of these disorders through the application of next-generation sequencing and related technologies, the pathogenicity of genetic variants and causes of learning and memory impairments can be difficult to determine from sequencing data alone. High-throughput genetic model organisms such as the roundworm Caenorhabditis elegans, fruit fly Drosophila melanogaster, and zebrafish Danio rerio offer low-cost and efficient methods to investigate the functions of identified neurodevelopmental disorder risk genes and the functional consequences of specific disorder-associated variants. Here, we review ways assessing habituation has been used in the genotype-first approach to first validate neurodevelopmental disorder candidate genes and now to systematically characterize large candidate gene lists. We then discuss exciting ways habituation, in combination with other techniques, can be used as a tool to assess the pathogenicity of putative genes and genetic variants, uncover and confirm molecular networks, and identify potential therapeutic avenues.