発達障害の病態理解に向けた統合的アプローチ
Integrative approach towards understanding pathophysiology of developmental brain disorders
S3-1-1-1
自閉症スペクトラム障害の病態理解を目指した15q重複モデルマウスの解析
A mouse model of 15q duplication syndrome towards understanding of molecular pathophysiology of autisms

○内匠透1
○Toru Takumi1
理化学研究所脳科学総合研究センター1
RIKEN, Brain Science Institute1

Recent advance in neuroscience reveals that psychiatric diseases may be based on synaptic abnormality. Autism spectrum disorders (ASD) are child psychiatric illnesses that are characterized by impairments in social interactions and verbal and non-verbal communications, and pervasive stereotypic behavior. Most of their causes are unknown, whereas there are several known causes of ASD, in syndromic cases (fragile X syndrome, tuberous sclerosis, Rett syndrome, etc.), chromosomal abnormality (15q11-13 duplication, other CNVs), and rare mutations. Among CNVs and rare mutations, cell adhesion molecules that are involved in synapse formation and other related molecules to synaptic functions are particularly intriguing. The cause of ASD may be considered as abnormality in postnatal development of synapses. We have generated a mouse model for duplication of human chromosome 15q11-13 using a chromosome-engineering technique. I will present our analyses on these mice towards understanding of molecular pathophysiology of ASD.
S3-1-1-2
自閉症モデル動物でのシナプス動態
Synapse dynamics in mouse models of autism

○岡部繁男1
○Shigeo Okabe1
東京大学大学院医学系研究科神経細胞生物学1
Dept Cellular Neurobiology, Univ. of Tokyo1

Cortical dysfunction is thought to underlie defects in social behaviors and communications in autism spectrum disorders (ASDs). Recent genetic studies of copy number variations and gene mutations have supported the hypothesis that nonsyndromic ASDs can be caused by structural or sequence variations in genes related to synapse development, including genes encoding cell adhesion molecules and scaffolding molecules. Alterations in circuit development caused by mutations in key molecules of synapse formation may underlie cortical dysfunction in ASDs. This hypothesis can be directly tested by imaging the developing synapses in ASD mouse models. In this study, we expressed PSD-95-GFP and the red fluorescent protein DsRed2 in mouse layer (L)2/3 pyramidal neurons using in utero electroporation. In vivo two-photon microscopy was performed over the anterior frontal cortex or the somatosensory cortex. The increase in synapses in the developing rodent neocortex has been reported to be more than 7-fold from postnatal day (PND) 6 to PND 21. We analyzed the turnover rate of spines and PSD-95-GFP clusters in the apical dendrites of L2/3 pyramidal neurons at PND 21 and detected alterations in spine/PSD dynamics common in three different ASD mouse models. In addition, detailed analyses of synapse dynamics revealed phenotypes specific to the individual mouse models. Our findings suggest that altered synapse dynamics is a common phenotype in the ASD mouse models and may trigger subsequent dysfunction of the neocortical circuitry, leading to defects in social behaviors and communications.
S3-1-1-3
扁桃体内側核のオキシトシン受容体を発現するニューロンと社会記憶
Social memory and neurons expressing oxytocin receptor in medial amygdala

○西森克彦1, 千葉裕太朗1, 佐藤佳亮1, 水上浩明2, 日出間志寿1
○Katsuhiko Nishimori1, Yutaro Chiba1, Keisuke Sato1, Hiroaki Mizukami2, Shizu Hidema1
東北大学大学院農学研究科分子生物学分野1, 自治医科大学分子病態治療研究センター2
Lab. of Mol. Biol., Grad. Sch. of Agric. Science, Tohoku Univ1, Dept. of Physiol., Jichi Medical University, , Shimotsuke, Tochigi2

Recent clinical trials by the administration of oxytocin (OXT) to ASD patients have been reported with positive aspects. However, the mechanism how OXT cured ASD has still not been well studied, except the distinctive notion that OXT might function via binding to its receptor, oxytocin receptor (OXTR), localized at various nuclei in the brain. However, the nuclei where OXTR was expressed, and the neural circuits, which were activated or suppressed by the nasal administration of OXT, leading to therapeutic effects, were wholly unaddressed. By generation of various types of pathophysiological model mice, whose OXT and OXTR genes were deleted or modified (1,2,3), we have studied the physiological function of OXT and OXTR, with focusing on the roles of those genes in the regulation of social behaviors. Resultantly, we found that neurons expressing OXTR were widely distributed in many nuclei in the brain, related to emotion and social behaviors (3). To understand the pleiotropically pharmaceutical action by OXT, such as anti-autistic effect, it is absolutely important to elucidate the specific nuclei where OXTR is expressed with critical functions on social behaviors and to specify the characteristics of those neurons expressing OXTR.Both of oxtr(-/-) mice and Oxt(-/-) mice showed impairment in social memory (2,4). Moreover, MeA-specific deletion of Oxtr also showed impaired social memory. Next, we tried to cure oxtr(-/-) mice using viral vector AAV-Oxtr-IRES-Venus, harboring OXTR. In the results, the rescuing of Oxtr gene to MeA nucleus in the brain of oxtr(-/-) mice showed recovered social memory. We hypothesize that oxtr(-/-) mice are pathophysiological models of human ASD, and our experiments suggest the importance of the OXTR expressed in MeA of mice for their social memory, and imply the importance of OXTR in MeA of human to understand ASD.1. PNAS. 93;11699, (1996)2. PNAS. 102;16096, (2005)3. J.Neuroscience 29;2259, (2009)4. Nature Genet.25; 284 (2000)
S3-1-1-4
22q11CNVに連鎖した神経発達障害のマウスモデル
Translating 22q11.2 CNV-associated developmental neuropsychiatric disorders into mouse models

○廣井昇1,2,3, 平本豪志1, ベッカアトマイケル2, カンジィナ1, 谷垣健二4, ぺナホゼ2, 高橋知久1, 朴秀賢1
○Noboru Hiroi1,2,3, Takeshi Hiramoto1, Michael Beckert2, Gina Kang1, Kenji Tanigaki4, Jose Pena2, Tomohisa Takahashi1, Shuken Boku1
, 滋賀県立成人病センター研究所4
Dept. Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine1, Dept. Neuroscience, Albert Einstein College of Medicine2, Dept. Genetics, Albert Einstein College of Medicine3, Shiga Medical Center, Moriyama, Shiga, Japan4

It has been difficult to translate symptoms of developmental neuropsychiatric disorders into mouse models partly because mouse behaviors do not faithfully mimic human symptoms (i.e., face validity) and the precise mechanisms of developmental neuropsychiatric disorders are still poorly understood (i.e., construct validity). However, recent discoveries of copy number variants (CNVs)--and their robust association with many developmental neuropsychiatric disorders--have provided an entry point to develop mouse models that partly satisfy construct validity. A CNV at 22q11.2 is reliably associated with extraordinarily high rates of autism spectrum disorder, schizophrenia, intellectual disability, attention deficit hyperactivity disorder, obsessive compulsive disorder and learning disabilities. However, as this CNV, like many other CNVs, includes many genes, the precise manner through which individual 22q11.2 genes confer heightened susceptibility to developmental neuropsychiatric disorders cannot be ascertained in humans. Our group has capitalized on this association and has ascertained small 22q11.2 segments and single genes whose dose alteration causes behavioral phenotypes in mouse models. In particular, we have shown that constitutive deficiency of Tbx1, one of the 22q11.2 genes, causes deficits in social interaction and communication, behavioral alternation (i.e., repetitive behavior) and working memory. Moreover, we have found that Tbx1 is required for postnatal neurogenesis, and have developed a mouse whose Tbx1 is conditionally deleted in postnatal neural progenitor cells. Work is in progress to identify behavioral phenotypes that uniquely depend on postnatal levels of Tbx1 in those cells. Our findings suggest that this gene contributes to postnatal neurogenesis and symptomatic elements of developmental neuropsychiatric disorders.
S3-1-1-5
自閉症スペクトラム障害の遺伝学的解析とシナプス
Genetic buffering and synaptic homeostasis in autism spectrum disorders

○Thomas Bourgeron1
Institut Pasteur, Paris, France1

The diagnosis of autism spectrum disorders (ASD) is based on impairments in reciprocal social communication, and repetitive behaviours. Our previous studies pointed at one synaptic pathway associated with the disorder. Among the causative genes, synaptic cell adhesion molecules (neuroligins and neurexins) and scaffolding proteins (SHANK3) are crucial for synapse formation/maintenance as well as correct balance between inhibitory and excitatory synaptic currents. In parallel, we identified genetic mutations that disrupt the serotonin-N-acetylserotonin-melatonin signalling in a subset of patients. This pathway is known to have pleiotropic effects, which include the regulation of circadian rhythms such as sleep-wake cycles, the modulation of synaptic circuits, as well as the protection against free radicals and brain injury. In this presentation, I will discuss our recent results coming from human genetics and mouse models studies that shed new light on the inheritance of ASD and on the phenotypic consequences of a synaptic defect. Based on these results, I propose that abnormal genetic buffering and synaptic homeostasis are risk factors for ASD. Genetic buffering is the ability of a genome to accumulate mutations without phenotypic impact. Synaptic homeostasis is the ability to regulate the level of synaptic strength through a cross talk between the pre- and post-synaptic sides. At the genome level, both the genetic background (the frequent variants observed in the genome) and the rare or private deleterious mutations might act in concert to increase the risk of ASD. Similarly at the synapse, both a weak homeostatic control and the presence of deleterious components of the synapse might act in concert to increase the risk of a synaptic disorder. If synaptic homeostasis is altered in ASD, environmental factors that influence this regulatory process could also modulate its severity.


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