Preprint
A hundred genes implicated in intellectual disability and autism regulate habituation learning and reveal an opposing role for Ras-MAPK signaling in inhibitory and excitatory neurons
20 Mar 2018
Abstract
Background Although habituation is one of the most ancient and fundamental forms of learning, its regulators and 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 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 more than 100 genes required for habituation learning. For the vast majority of these, 93 genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with overgrowth/macrocephaly and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response.
Conclusions Our work demonstrates the relevance of habituation learning to autism, 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. This establishes habituation as a possible, widely applicable target for pharmacologic intervention in ID/ASD.
Metrics
25 Record Views
Details
- Title
- A hundred genes implicated in intellectual disability and autism regulate habituation learning and reveal an opposing role for Ras-MAPK signaling in inhibitory and excitatory neurons
- Creators
- Michaela Fenckova - Radboud University Medical CenterLaura E. R. Blok - Radboud University Medical CenterLenke Asztalos - University of CambridgePavel Cizek - Radboud University Medical CenterEuginia L. Singgih - Radboud University Medical CenterJeffrey C. Glennon - Radboud University Medical CenterJoanna Inthout - Radboud University Medical CenterChristiane Zweier - Friedrich-Alexander-Universität Erlangen-NürnbergEvan E. EichlerRaphael A. BernierZoltan Asztalos - University of CambridgeCatherine R von Reyn - Drexel University, School of Biomedical Engineering, Science, and Health SystemsAnnette Schenck (Corresponding Author) - Radboud University Medical Center
- Publisher
- American Physical Society (APS)
- Resource Type
- Preprint
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Other Identifier
- 991019287814204721