公募シンポジウム５：神経精神疾患の病態とその分子基盤：若手研究者によるアプローチ
Symposium5 : Pathophysiology and molecular mechanisms of neuropsychiatric disorders: Approaches by young investigators |
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| 2020/9/10 16:12～16:34 Zoom B
SY5-01
患者iPS細胞で明らかにする神経精神疾患の細胞・分子病理
Patient-derived iPS cells reveal the cellular pathophysiology of neuropsychiatric disorders
*有岡 祐子1
1. 名古屋大学医学部附属病院
*Yuko Arioka1
1. Nagoya University Hospital
Human genomic studies of patients with neuropsychiatric disorders have identified many possible factors, such as rare genomic variants, that strongly contribute to the onset of neuropsychiatric disorders. However, their cellular and molecular mechanisms remain unclear. To address this, we use patient iPS cells (iPSCs) with such genomic variants. For example, we identified a schizophrenia patient with a rare RELN deletion and generated this patient iPSCs. RELN is one of the genes relevant to neuropsychiatric disorders and plays an important role during brain development. We revealed that this patient iPSC-derived neurons show the unstable neuronal migration even at the single-cell level (Arioka Y et al. Transl Psychiatry 2018;8:129, Arioka Y et al. Sci Rep. 2020;10(1):5820). Our unique automated detection and analysis system of imaging data enabled us to capture the behavior of individual cells. Currently, we focus on chromosome 22q11.2 deletion. This deletion is a high-risk factor leading to the onset of various neuropsychiatric disorders; neurodegenerative disorders such as Parkinson's disease as well as mental disorders such as schizophrenia and autism spectrum disorder. In this symposium, we will introduce our research on neuropsychiatric disorders based on genomic analysis and discuss the advantages of, as well as issues remaining to be solved for, the use of iPSCs.
| | 2020/9/10 16:34～16:56 Zoom B
SY5-02
うつ病モデル動物における脳白質の異常
White matter abnormalities in animal model of depression: Possible underlying mechanisms
*國澤 和生1、飯田 翼1、齊藤 成1、小菅 愛加1、ウラル ポラテ1、ウィリージャヤ スエント1,2、山本 康子1、齋藤 邦明1,3、毛利 彰宏1,3、鍋島 俊隆1,3
1. 藤田医科大学、2. ハサヌディン大学、3. NPO法人医薬品適正使用推進機構
*Kazuo Kunisawa1, Tsubasa Iida1, Sei Saitoh1, Aika Kosuge1, Bolati Wulaer1, Willy Jaya Suento1,2, Yasuko Yamamoto1, Kuniaki Saito1,3, Akihiro Mouri1,3, Toshitaka Nabeshima1,3
1. Fujita Health University, 2. Hasanuddin University, 3. Japanese Drug Organization of Appropriate Use and Research
White matter abnormalities have been implicated in psychiatric diseases such as major depressive disorder (MDD); however, the underlying mechanisms remain poorly understood. The structure and function of the corpus callosum are particularly vulnerable to stress effects, which may lead to MDD. In the present study, we investigated whether chronic social defeat stress (CSDS) induces myelin abnormalities of the corpus callosum through inflammation that contribute to the pathogenesis of MDD. The adult C57BL/6J mouse was exposed CSDS by aggressor ICR mouse for 10 consecutive days. One and 28 days after the last CSDS, mice were subjected to the social interaction test and forced swimming test to confirm that the mice developed depression-like behaviors. Transmission electron microscopy was used to investigate the myelin morphology in the corpus callosum of these mice. CSDS decreased mature oligodendrocytes in the corpus callosum, and persistently developed depression-like behaviors such as impaired social interaction and increased immobility in the forced swimming test. By using transmission electron microscopy, we observed myelin abnormalities and axonal degeneration in the corpus callosum. Interestingly, CSDS elicited microglial engulfment of myelin sheaths concomitantly with increased IL-1β production in the corpus callosum. Administration of IL-1β inhibitor prevented CSDS-induced depression-like behaviors. These findings suggest that IL-1β acts as a crucial mediator of myelin abnormalities induced by the CSDS, which may be responsible for the development of MDD.
| | 2020/9/10 16:56～17:18 Zoom B
SY5-03
新規うつ病治療標的としてのセロトニン5-HT2A受容体の有用性
Validity of serotonin 5-HT2A receptor as a new therapeutic target to depression
*衣斐 大祐1
1. 名城大学
*Daisuke Ibi1
1. Meijo Univ.
About 30% of the patients with depression is considered treatment resistant despite the optimal antidepressant use. Ketamine, a NMDA receptor antagonist, is effective for treatment-resistant depression, but it has severe aversive effects including addiction. Recent studies have reported that serotonin 5-HT2A receptor (5-HT2A) agonist has rapid-acting and long-lasting antidepressant effect for treatment-resistant depression. Further, occurrence frequency of 5-HT2A agonist adverse effect such as hallucination would be less than ketamine although the molecular mechanisms underlying antidepressant effect of 5-HT2A agonist remains unclear. Here, we investigated validity and mechanisms of a 5-HT2A agonist antidepressant effect. We examined an antidepressant effect of 5-HT2A agonists in mice, in which mice showed the decreased immobility time in the forced-swim test (FST) 24 hr after acute treatment of 5-HT2A agonists, DOI, TCB2 and psilocin, which was completely inhibited by pre-treatment of a 5-HT2A antagonist, volinanserin. Next, to investigate the brain region involved in the antidepressant effect of 5-HT2A agonists, mice with treatment of 5-HT2A agonist were sacrificed for c-Fos staining 60 min after FST. We found that an increase in the number of c-Fos-positive cells in GABAergic neurons of the lateral septum (LS) of mice treated with DOI, which was also suppressed by pre-treatment of volinanserin. Further, we tested the effect of DOI in an animal model of depression with chronic corticosterone (CORT) treatment. Mice with chronic CORT treatment exhibited depressive-like behaviors and social interaction deficits as well as decrease in c-Fos-positive cells in LS, which were ameliorated by acute DOI treatment, suggesting that antidepressant effect of 5-HT2A agonist is associated with activation of GABAergic neurons in the LS.
| | 2020/9/10 17:18～17:40 Zoom B
SY5-04
自閉スペクトラム症における社会性障害の神経基盤
Decodeing neural basis underlying social difficulties in autism spectrum disorders
*臼井 紀好1,2,3
1. 阪大院・医・共同研、2. 阪大院・医・神経細胞生物、3. 阪大・国際医工情報
*Noriyoshi Usui1,2,3
1. CentMeRE, Grad Sch Med, Osaka University, 2. Dept Neurosci Cell Biol, Grad Sch Med, Osaka University, 3. Global Ctr Med Eng Inform, Osaka University
Autism spectrum disorder (ASD) is a developmental disorder characterized by abnormalities in social interaction and communication as well as repetitive behaviors and restricted interests, and hyperesthesia and hypesthesia. ASD has been studied all over the world, and despite the fact that more than 1000 related genes have been identified to date, no clear neural basis for the symptoms has been identified, nor has an effective biomarker or treatment been established. We have investigated the neural basis regulating the sociability by focusing on several ASD causative genes such as FOXP1 and FOXP2 using cultured human neurons and mice as models. As another approach, in order to understand the sociality, we have been also investigating 1) the human brain evolution, and 2) a mouse model that manipulated the social environment. In this symposium, we will discuss our latest findings on the neural basis of social impairments in ASD, including our previous findings and current studies.
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