共同企画

共同企画合同シンポジウム自閉スペクトラム症研究の最前線

7月8日（土）　8:30-10:30　Room A 3JS①-1 Elucidation of pathogenesis for Autism spectrum disorder from rare variants with a large effect size 尾崎　紀夫名古屋大学大学院医学系研究科　精神疾患病態解明学 Norio Ozaki Pathophysiology of Mental Disorders, Nagoya University Graduate School of Medicine We performed the cross-disorder analysis of copy number variants (CNVs) in autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BD). Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and ASD/SCZ differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, ASD and SCZ involved more extensive and similar pathways. Autism Sequencing, Consortium in which we participate, performed the large exome sequencing study of ASD. Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.We have also tried to elucidate pathophysiology by utilizing ASD models, such as a genome-edited mouse or induced pluripotent stem cells based on the rare variants with large effect sizes.		7月8日（土）　8:30-10:30　Room A 3JS①-2 自閉スペクトラム症の環境要因 The environmental factors in autism spectrum disorders 松崎　秀夫¹ 1. 福井大学・子どものこころの発達研究センター, 2. 大阪大学大学院・連合小児発達学研究科 Hideo Matsuzaki¹ 1. Research Center for Child Mental Development, University of Fukui, Fukui, Japan, 2. United Graduate School of Child Development, Osaka University, Suita, Osaka Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder clinically characterized by impaired communication, impaired social interaction, restricted interests and behaviours, and sensory features. In recent years, the increasing prevalence of autism has attracted social attention. The etiology of ASD is still unknown, and so far, onset factors have been investigated from both congenital genetic factors and acquired environmental factors. In recent years, the main hypothesis of ASD etiology is that epigenetic dysfunction causes specific synapse abnormalities and E/I imbalance in neural network in the brain as a result of the interaction between genes and the environment at development. Therefore, it is important "when" and "where" environmental factors affect the central nervous system and initiate developmental changes, with regarding the problem of environmental factors in ASD. Since the diagnostic criteria for ASD include the onset of symptoms seen in early development, many environmental factors in the developmental process up to birth have been verified, and many reports suggest the insight that the abnormalities onset at early pregnancy in ASD. This presentation will introduce the environmental factors that have been discussed with ASD, focusing on drugs, viral infections, vaccines, endocrine disruptors, and oxidative stress.

7月8日（土）　8:30-10:30　Room A 3JS①-3 自閉スペクトラム症感受性遺伝子AUTS2の神経細胞産生における分子機能と病態解明 Molecular function and pathogenesis of AUTS2 in neurogenesis 嶋岡　可純¹, 堀　啓¹, 井上　由紀子¹, 郷　康広², 阿部　学³, 崎村　建司³, 井上　高良¹, 星野　幹雄¹ 1. 国立精神・神経セ・神経研・病態生化学, 2. 生理研・発達生理認知行動発達, 3. 新潟大・脳研・基礎神経科学細胞神経生物 Kazumi Shimaoka¹, Kei Hori¹, Yukiko Inoue¹, Yasuhiro Go², Manabu Abe³, Kenji Sakimura³, Takayoshi Inoue¹, Mikio Hoshino¹ 1. Dept. of Biochem. & Cell. Biol., NCNP, Tokyo, 2. Dept., of Brain Sci., Center for Novel Sci Initiative, NIPS, Okazaki, Aichi, 3. Dept., of Cell. Neurobiol., BRI, Univ. of Niigata Autism susceptibility candidate 2 (AUTS2) has been implicated as the gene associated with numerous psychiatric disorders such as autism spectrum disorders (ASDs), intellectual disabilities (ID) and schizophrenia. In addition, patients with AUTS2 mutation often have features such as microcephaly and craniofacial dysmorphisms. We have previously showed that Auts2 knockout (KO) mice have impaired sociality and memory. With respect to AUTS2 function, it has been reported that cytoplasmic AUTS2 regulates cytoskeleton and nuclear AUTS2 activates transcription together with Polycomb repressive complex 1 (PRC1). However, there remain many questions about the physiological roles of AUTS2 in the brain development. Here, we will show a novel function of AUTS2 in neurogenesis. In Auts2 KO mice, we found that upper-layer neurons in cerebral cortex were reduced. This was caused by a decrease in intermediate progenitor cell (IPC) division. RNA-seq and CUT&Tag analysis in IPCs showed that the expression of genes related to neuron differentiation was increased and histone modifications were altered to the active chromatin state in mutant IPCs. Together, our findings suggest that AUTS2 functions as a transcriptional repressor by maintaining histone modifications in a repressive state and contributes to the production of an appropriate number of neurons by promoting IPC division.		7月8日（土）　8:30-10:30　Room A 3JS①-4 ヒト型モデル動物を用いた自閉症の神経回路の同定と治療法開発への応用 Identification of neural circuitry in autism spectrum disorder using human-animal models 西山　正章金沢大学医薬保健研究域医学系　組織細胞学 Masaaki Nishiyama Dept. Hist. Cell Biol., Grad. Sch. Med. Sci., Kanazawa Univ. Recently, a large-scale search has been conducted for the causative genes of autism spectrum disorder (ASD), and the chromatin remodeling factor CHD8 was identified as the most promising candidate causative gene. However, the types of neural cells responsible for behavioral abnormalities in ASD remained unclear. Gene expression analysis of Chd8 heterozygous deletion mice showed that genes related to oligodendrocytes were most significantly down-regulated. Chd8 heterozygous mice and oligodendrocyte-specific Chd8 heterozygous deletion mice showed reduced myelin formation, abnormal Ranvier structure, and reduced nerve conduction velocity. Furthermore, abnormal social behavior and increased anxiety-like behavior observed in whole-body Chd8 heterozygous deletion mice were recapitulated. Oligodendrocyte-specific Chd8 heterozygous deficient mice were then evaluated by magnetic resonance imaging (MRI) analysis. Diffusion tensor images showed that the microstructure of specific brain regions, including the cortex and striatum, was altered in Chd8 heterozygous mice. Resting-state functional MRI showed altered functional connectivity of the brain, and the extent of these changes was correlated with changes in social behavior. These results suggest that dysfunctional oligodendrocytes affect neural networks and contribute to ASD.

7月8日（土）　8:30-10:30　Room A 3JS①-5 自閉症の物質的基盤 Genomic basis of autism 内匠　透神戸大院・医・生理 Toru Takumi Kobe Univ Sch Med Autism spectrum disorder (ASD) is a complex psychiatric illness that has received considerable attention as a developmental brain disorder. Substantial evidence suggests that chromosomal abnormalities, including copy number variations (CNV), contribute to autism risk. The duplication of human chromosome 15q11-13 is the most frequent cytogenetic abnormality in ASD. We modeled this genetic change in mice using chromosome engineering to generate a 6.3-Mb duplication of the conserved linkage group on mouse chromosome 7. This chromosome-engineered mouse model for ASD (15q dup mouse) seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human CNV. This 15q dup mouse is the first CNV model of ASD and a founder mouse for forward genetics of a developmental brain disorder. Our multi-dimensional approach reveals that 15q dup mice show impaired spine phenotypes, abnormality in serotonin, and excitatory/inhibitory imbalance. Screening the essential gene in the duplicated region using spine phenotypes identified Necdin as a driver gene. We also developed ES models with CNVs using next-generation chromosome engineering. I’ll talk about these analyses of mouse and cellular models of CNVs focusing on the recent data, hopefully adding our new direction towards understanding the pathophysiology of ASD.