Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

Significance Extensive efforts have been devoted to revealing the cognitive and molecular bases of autism spectrum disorders. In this work, by using a reversal-learning paradigm that measures behavioral flexibility in Drosophila, we show that flies with mutations of five autism susceptibility genes—Fragile X mental retardation 1, Ubiquitin-protein ligase E3A, Neurexin-1, Neuroligin 4, and Tuberous sclerosis complex 1—displayed severe reversal-learning defects which were caused by the inability to forget the previously formed memory by the activation of Rac1 (Ras-related C3 botulinum toxin substrate 1). These findings indicate that Rac1-dependent forgetting is a functional converging point for multiple autism-risk genes. 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.