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Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders.

ABSTRACT: BACKGROUND:Although habituation is one of the most ancient and fundamental forms of learning, its regulators and its relevance for human disease are poorly understood. METHODS:We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and we tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies, and interaction networks to determine the clinical features and molecular processes that are associated with habituation deficits. RESULTS:We identified >100 genes required for habituation learning. For 93 of these genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly and/or overgrowth and comorbid ASD. Moreover, individuals with ASD from the Simons Simplex Collection carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras/mitogen-activated protein kinase (Ras/MAPK) signaling. Both increased Ras/MAPK signaling in gamma-aminobutyric acidergic (GABAergic) neurons and decreased Ras/MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response. CONCLUSIONS:Our work supports the relevance of habituation learning to ASD, identifies an unprecedented number of novel habituation players, supports an emerging role for inhibitory neurons in habituation, and reveals an opposing, circuit-level-based mechanism for Ras/MAPK signaling. These findings establish habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD.

SUBMITTER: Fenckova M

PROVIDER: S-EPMC7053436 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders.

Fenckova Michaela M Blok Laura E R LER Asztalos Lenke L Goodman David P DP Cizek Pavel P Singgih Euginia L EL Glennon Jeffrey C JC IntHout Joanna J Zweier Christiane C Eichler Evan E EE von Reyn Catherine R CR Bernier Raphael A RA Asztalos Zoltan Z Schenck Annette A

Biological psychiatry 20190509 4

<h4>Background</h4>Although habituation is one of the most ancient and fundamental forms of learning, its regulators and its relevance for human disease are poorly understood.<h4>Methods</h4>We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and we tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation def ...[more]

PMID: 31272685

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Project description:BackgroundMaternal diabetes has been associated with a risk of neurodevelopmental disorders (NDDs) in offspring, though the common co-occurrence of autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID) is rarely considered, nor is the potential for confounding by shared familial factors (e.g. genetics).MethodsThis population-based cohort study used data from Psychiatry Sweden, a linkage of Swedish national registers, to follow 2 369 680 individuals born from 1987 to 2010. We used population-averaged logit models to examine the association between exposure to maternal type 1 diabetes mellitus (T1DM), pre-gestational type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM), and odds of NDDs in offspring. Subgroup analysis was then performed to investigate the timings of GDM diagnosis during pregnancy and its effect on the odds of NDDs in offspring. We compared these results to models considering paternal lifetime T1DM and T2DM as exposures.ResultsOverall, 45 678 individuals (1.93%) were diagnosed with ASD, 20 823 (0.88%) with ID and 102 018 (4.31%) with ADHD. All types of maternal diabetes were associated with odds of NDDs, with T2DM most strongly associated with any diagnosis of ASD (odds ratioadjusted 1.37, 95% confidence interval 1.03-1.84), ID (2.09, 1.53-2.87) and ADHD (1.43, 1.16-1.77). Considering common co-morbid groups, the associations were strongest between maternal diabetes and diagnostic combinations that included ID. Paternal T1DM and T2DM diagnoses were also associated with offspring NDDs, but these associations were weaker than those with maternal diabetes. Diagnosis of GDM between 27 and 30 weeks of gestation was generally associated with the greatest risk of NDDs in offspring, with the strongest associations for outcomes that included ID.ConclusionThe association of maternal diabetes with NDDs in offspring varies depending on the co-morbid presentation of the NDDs, with the greatest odds associated with outcomes that included ID. Results of paternal-comparison studies suggest that the above associations are likely to be partly confounded by shared familial factors, such as genetic liability.

Project description:ImportanceDepression is a frequently occurring mental disorder and may be common in adults with autism spectrum disorders (ASD), but there is a lack of longitudinal population-based studies examining this association. Whether any increased risk of depression in ASD has a shared familial basis and whether it differs by co-occurring intellectual disability is not well known.ObjectivesTo examine whether individuals with ASD are more likely to be diagnosed as having depression in adulthood than the general population and their nonautistic siblings and to investigate whether these risks differ by the presence or absence of intellectual disability.Design, setting, and participantsPopulation-based cohort study with a nested sibling comparison. The Stockholm Youth Cohort is a total population record linkage study that includes all children and young people (age range, 0-17 years) who were ever resident in Stockholm County, Sweden, between January 2001 and December 2011 (n?=?735?096). Data analysis was conducted between January 5 and November 30, 2017, in Stockholm County, Sweden.Main outcomes and measuresClinical diagnosis of depressive disorders was identified using the Stockholm County Adult Psychiatric Outpatient Register and the Swedish National Patient Register.ResultsParticipants were 223?842 individuals followed up to age 27 years by 2011, of whom 4073 had diagnosed ASD (mean [SD] age, 21.5 [2.7] years; 65.9% male; 2927 without intellectual disability and 1146 with intellectual disability) and 219?769 had no ASD (mean [SD] age, 22.1 [2.8] years; 50.9% male). By age 27 years, 19.8% (n?=?808) of individuals diagnosed having ASD had a diagnosis of depression compared with 6.0% (n?=?13?114) of the general population (adjusted relative risk [RR], 3.64; 95% CI, 3.41-3.88). The risk of a depression diagnosis was higher in ASD without intellectual disability (adjusted RR, 4.28; 95% CI, 4.00-4.58) than in ASD with intellectual disability (adjusted RR, 1.81; 95% CI, 1.51-2.17). Nonautistic full-siblings (adjusted RR, 1.37; 95% CI, 1.23-1.53) and half-siblings (adjusted RR, 1.42; 95% CI, 1.23-1.64) of individuals with ASD also had a higher risk of depression than the general population. Compared with their nonautistic full-siblings, individuals with ASD had more than a 2-fold risk of a depression diagnosis (adjusted odds ratio, 2.50; 95% CI, 1.91-3.27) in young adulthood.Conclusions and relevanceAccording to this study's results, ASD, particularly ASD without intellectual disability, is associated with depression by young adulthood compared with the general population. It appears that this association is unlikely to be explained by shared familial liability. Future research to identify modifiable pathways between ASD and depression may assist in the development of preventive interventions.

Dataset Information

Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders.

Publications

Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders.

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