Systematic phenomics analysis of ASD-associated genes reveals shared functions and parallel networks underlying reversible impairments in habituation learning

McDiarmid, Troy A.; Belmadani, Manuel; Liang, Joseph; Meili, Fabian; Mathews, Eleanor; Mullen, Gregory P.; Rand, James B.; Mizumoto, Kota; Haas, Kurt; Pavlidis, Paul; Rankin, Catharine H.

doi:10.1101/687194

Cited by 4 publications

(2 citation statements)

References 173 publications

(199 reference statements)

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“…Previous studies have used C. elegans morphology and locomotion as readouts of disrupted behaviour in response to mutation to ASD associated genes (31,32). We have extended this analysis to inform on the effect of a neuroligin variant on a phenotype that relates to one of the triad of impairments that make up the diagnostic criteria of ASD.…”

Section: Discussionmentioning

confidence: 99%

Neuroligin dependence of social behaviour inCaenorhabditis elegansprovides a model to investigate an autism-associated gene

Rawsthorne

Calahorro

Feist

et al. 2020

Human Molecular Genetics

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Autism spectrum disorder (ASD) is characterised by a triad of behavioural impairments including social behaviour. Neuroligin, a trans-synaptic adhesion molecule, has emerged as a penetrant genetic determinant of behavioural traits that signature the neuroatypical behaviours of autism. However, the function of neuroligin in social circuitry and the impact of genetic variation to this gene is not fully understood. Indeed, in animal studies designed to model autism there remains controversy regarding the role of neuroligin dysfunction in the expression of disrupted social behaviours. The model organism, C. elegans, offers an informative experimental platform to investigate the impact of genetic variants on social behaviour. In a number of paradigms it has been shown that inter-organismal communication by chemical cues regulates C. elegans social behaviour. We utilise this social behaviour to investigate the effect of autism associated genetic variants within the social domain of the research domain criteria. We have identified neuroligin as an important regulator of social behaviour and segregate the importance of this gene to the recognition and/or processing of social cues. We also use CRISPR/Cas9 to edit an R-C mutation that mimics a highly penetrant human mutation associated with autism. C. elegans carrying this mutation phenocopy the behavioural dysfunction of a C. elegans neuroligin null mutant, thus confirming its significance in the regulation of animal social biology. This highlights that quantitative behaviour and precision genetic intervention can be used to manipulate discrete social circuits of the worm to provide further insight to complex social behaviour.

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Section: Discussionmentioning

confidence: 99%

Neuroligin dependence of social behaviour inCaenorhabditis elegansprovides a model to investigate an autism-associated gene

Rawsthorne

Calahorro

Feist

et al. 2020

Human Molecular Genetics

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“…Although this learning process appears simple at first glance, previous work revealed that at least long-term habituation learning is regulated by multiple mechanisms that operate on distinct time scales 2,15 . Similarly, numerous molecular-genetic mechanisms also regulate short-term habituation learning [16][17][18][19][20][21][22][23][24][25][26] . Moreover, pharmacological screens have identified multiple neurotransmitter and neuromodulatory systems contributing to habituation 7 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic and whole-brain activity analyses uncover integration of distinct molecular and circuit programs that drive learning

Nelson

Shoenhard

Granato

2022

Preprint

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Habituation is a foundational learning process critical for animals to adapt their behavior to changes in their sensory environment. Although habituation is considered a simple form of learning, the identification of a multitude of molecular pathways including several neurotransmitter systems that regulate this process suggests an unexpected level of complexity. How the vertebrate brain integrates these various pathways to accomplish habituation learning, whether they act independently or intersect with one another, and whether they act via divergent or overlapping neural circuits has remained unclear. To address these questions, we combined pharmacogenetic pathway analysis with unbiased whole-brain activity mapping using the larval zebrafish. This approach revealed five distinct molecular and circuit modules that regulate habituation learning and identified a set of molecularly defined brain regions associated with four of the five modules. Moreover, we find that in module 1 the palmitoyltransferase Hip14 cooperates with dopamine and NMDA signaling to drive plasticity, while in module 3 the adaptor protein complex subunit Ap2s1 drives habituation by antagonizing dopamine signaling, revealing two distinct and opposing roles for dopaminergic neuromodulation in the regulation of learning. Combined, our results define a core set of distinct modules that act in concert to regulate learning-associated plasticity, and provide compelling evidence that even seemingly simple learning behaviors in a compact vertebrate brain are regulated by a complex and overlapping set of molecular and circuit mechanisms.

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Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation

McDiarmid

Belmadani

Liang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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A major challenge facing the genetics of autism spectrum disorders (ASDs) is the large and growing number of candidate risk genes and gene variants of unknown functional significance. Here, we usedCaenorhabditis elegansto systematically functionally characterize ASD-associated genes in vivo. Using our custom machine vision system, we quantified 26 phenotypes spanning morphology, locomotion, tactile sensitivity, and habituation learning in 135 strains each carrying a mutation in an ortholog of an ASD-associated gene. We identified hundreds of genotype–phenotype relationships ranging from severe developmental delays and uncoordinated movement to subtle deficits in sensory and learning behaviors. We clustered genes by similarity in phenomic profiles and used epistasis analysis to discover parallel networks centered onCHD8•chd-7andNLGN3•nlg-1that underlie mechanosensory hyperresponsivity and impaired habituation learning. We then leveraged our data for in vivo functional assays to gauge missense variant effect. Expression of wild-type NLG-1 innlg-1mutantC. elegansrescued their sensory and learning impairments. Testing the rescuing ability of conserved ASD-associated neuroligin variants revealed varied partial loss of function despite proper subcellular localization. Finally, we used CRISPR-Cas9 auxin-inducible degradation to determine that phenotypic abnormalities caused by developmental loss of NLG-1 can be reversed by adult expression. This work charts the phenotypic landscape of ASD-associated genes, offers in vivo variant functional assays, and potential therapeutic targets for ASD.

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Systematic phenomics analysis of ASD-associated genes reveals shared functions and parallel networks underlying reversible impairments in habituation learning

Cited by 4 publications

References 173 publications

Neuroligin dependence of social behaviour inCaenorhabditis elegansprovides a model to investigate an autism-associated gene

Neuroligin dependence of social behaviour inCaenorhabditis elegansprovides a model to investigate an autism-associated gene

Pharmacogenetic and whole-brain activity analyses uncover integration of distinct molecular and circuit programs that drive learning

Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation

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