title: Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes.
abstract: The etiology of autism is so complicated because it involves the effects of variants of several hundred risk genes along with the contribution of environmental factors. Therefore, it has been challenging to identify the causal paths that lead to the core autistic symptoms such as social deficit, repetitive behaviors, and behavioral inflexibility. As an alternative approach, extensive efforts have been devoted to identifying the convergence of the targets and functions of the autism-risk genes to facilitate mapping out causal paths. In this study, we used a reversal-learning task to measure behavioral flexibility in Drosophila and determined the effects of loss-of-function mutations in multiple autism-risk gene homologs in flies. Mutations of five autism-risk genes with diversified molecular functions all led to a similar phenotype of behavioral inflexibility indicated by impaired reversal-learning. These reversal-learning defects resulted from the inability to forget or rather, specifically, to activate Rac1 (Ras-related C3 botulinum toxin substrate 1)-dependent forgetting. Thus, behavior-evoked activation of Rac1-dependent forgetting has a converging function for autism-risk genes.
authors.affiliation: Tsinghua-Peking Center for Life Sciences, McGovern Institute for Brain Research, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China;
authors.forename: Tao
authors.initials: T
authors.lastname: Dong
authors.affiliation: College of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.affiliation: Tsinghua-Peking Center for Life Sciences, McGovern Institute for Brain Research, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China;
authors.forename: Shiqing
authors.initials: S
authors.lastname: Wang
authors.affiliation: Tsinghua-Peking Center for Life Sciences, McGovern Institute for Brain Research, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China;
authors.forename: Lianzhang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming 650032, China;
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Tsinghua-Peking Center for Life Sciences, McGovern Institute for Brain Research, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China; Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China zhongyi@tsinghua.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D009154:Mutation; D012193:Reversal Learning; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000502:physiology*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D044767:Ubiquitin-Protein Ligases; D020830:rac1 GTP-Binding Protein; C467328:FMR1 protein, Drosophila; C584506:Nlg4 protein, Drosophila; C491321:Nrx protein, Drosophila; C515347:TSC1 protein, Drosophila; C532444:Ube3a protein, Drosophila
keywords: Drosophila; Rac1; autism; behavioral flexibility; forgetting