Paper

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

Zweier, Christiane, Eichler, Evan E, Goodman, David P, Bernier, Raphael, Asztalos, Lenke, Singgih, Euginia L, Asztalos, Zoltan, Laura Er Blok, Cizek, Pavel, Fenckova, Michaela, Von Reyn, Catherine R, Glennon, Jeffrey C, Schenck, Annette, Inthout, Joanna

2019

Overview

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 macrocephaly/overgrowth and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection (SSC) 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-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 supports 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 functional readout and target for pharmacologic intervention in ID/ASD.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Autism / Comorbidity / Genotypes / Habituation / Learning / Macrocephaly / MAP kinase / Neurons / Neuroscience / Phenotypes / γ-Aminobutyric acid