Symposium

Symposium 21 Understanding of Psychiatric Disease using postmortem brain-Hope for Japanese Psychiatric Brain Bank- シンポジウム21 精神疾患を死後脳から解明する　ー精神科ブレインバンクへの期待ー

SY21-1 Is really Schizophrenia the graveyard for Neuropathologist ? 統合失調症は、本当に神経病理学者にとって墓場か？ Iritani Shuji（入谷修司） Department of Psychiatry, Graduate school of Medicine, Nagoya University As one of the founders of German psychiatry, W. Griesinger (1817~1868), mentioned that mental illness is a disease of the brain promoting the place of psychiatry among modern medicine, that led to the current biological psychiatry. With this concept, Emil Kraepelin (1856~1926), who laid the foundation for German psychiatry, aimed at elucidating the biological causes of mental disorders. In the Japanese modernization era, many Japanese psychiatrists studied in Germany and absorbed German psychiatry. One of the persons who acted as a driving force was S. Kure (1865~1932). He promoted brain pathology research in the psychiatric field in Japan. Whereas much progress had made in neurodegeneration research, there hardly progress in the research of functional mental illness including schizophrenia using neuropathological approaches. After all, it has been said schizophrenia is a graveyard for neuropathologists ironically. From the 1980s, morphological changes in schizophrenic brain were reported by neuroimaging studies conducted one after another. In addition, it was said that when genes composing the brain, i.e. blueprint of brain tissue, are clarified with the progression of molecular psychiatry, the causes of mental diseases will be elucidated. Actually, several candidate genes such as DISC1 were discovered in schizophrenia patients, and the involvement of many functions of these genes in neural network formation has been clarified. On the other hand, the progress in neurochemical, neuroanatomical technique could extract many information from brain tissue in this decade. It would be important to focus on brain tissue in research of pathogenesis of functional mental illness with convergence in molecular biology, neuroimaging and neuropathology.		SY21-2 System Pathology of Schizophrenia and Its Animal Models 統合失調症とそのモデル動物のシステム病態学 Nawa Hiroyuki（那波宏之）¹，柿田明美² ¹Dept of Neurobiol, Brain Res Inst, Niigata Univ ²Dept of Pathology, Brain Res Inst, Niigata Univ, Niigata JAPAN 最近のシステム生理学の発展により「聞く」「見る」など認知機能には　上位中枢からのTOP　DOWN予測情報と感覚器からのBOTTOM UP知覚情報の統合が必要と言われている。その仮説によると、幻聴や幻覚、認知障害などの統合失調症の病態はTOP　DOWN予測情報の過剰、もしくは感覚器からのBOTTOM UP知覚情報の欠落によって起きると説明されている。それでは、この仮説は、どれくらい科学的に裏付けられるのであろうか？　本シンポジウムでは、統合失調症の死後脳研究結果とサイトカイン投与で作成された同疾患のモデル動物における最近の知見を踏まえて、この仮説を考察してみたい。サイトカインを生後時期に皮下投与して作製した我々のモデル動物は　動物種を問わず、錯乱もしくはせん妄様の認知行動異常が思春期以降に発現し、その多くが脳内ドパミン神経の発達性活動亢進を示す。ドパミンの脳内神経支配は前頭前野をはじめとする前頭部に集中しているので、TOP　DOWNシグナルを強化しているものと解釈される。実際にもECoG測定によると当該モデル動物のBOTTOM UPシグナルは弱い。同様の議論が統合失調症の脳機能画像研究でも提唱されており、BOTTOM UP知覚情報を淘汰して、前頭葉活動が聴覚野や視覚野の神経活動を実際に引き起こし、幻聴や幻覚を体験させると説明されてきた。確かに、我々のラットモデルでは聴覚野の過活動が恒常的に存在し、その活動の由来はドパミン過剰による前頭葉からのTOP　DOWNシグナル過剰と推定できる結果を得ている。興味深いことには、死後脳研究でも、統合失調症患者の聴覚野の神経活動マーカーの上昇がみられ、この仮説を裏付けているように思えることである。このように死後脳研究は、ヒトにおける脳病態情報を動物データにトランスレートできる貴重なアプローチであり、今後、死後脳コネクトーム技術の開発が待ち望まれる。なお、研究利用させていただいた凍結死後脳組織は所属機関のもののほかに、福島県立医大、都立松沢病院、神戸大学、名古屋大学などの外部機関との共同研究により分与されたものである。

SY21-3 Requirement of postmortem brain research in the psycopharmacological study of a novel molecule, Piccolo 新規精神疾患関連分子の生理機能解明およびモデル動物作成に向けての基礎研究における死後脳の重要性 Nitta Atsumi（新田淳美），宮本嘉明 Dept. Pharmaceutical Therapy Neuropharmacol, Fac Pharmaceutical Sci. Gra Sch Med Pharmaceutical Sci. Uni of Toyama We found three now molecules from nucleus accumbens of a schizophrenic animal model. He I would like to introduce postmortem brain research for Piccolo study. Piccolo, a presynaptic cytomatrix protein encoded by the PCLO gene, serves with synaptic exocytosis and endocytosis. In this study, we investigated the causal relationship between Piccolo expression and schizophrenia using mice. Like the aforementioned in vitro study, the protein expression levels of Piccolo increased in the amygdala of mice repeatedly treated with risperidone, an atypical antipsychotic drug, but not haloperidol, a typical antipsychotic drug. These findings suggest that elevated PCLO mRNA in the postmortem brain of schizophrenia patients is due to the therapeutic efficacy, rather than the pathogenesis of schizophrenia. Next, we investigated the phenotypical changes in mice with Piccolo knockdown in the amygdala. To generate animals with reduced Piccolo expression, we injected AAV-miPCLO vector into the amygdala of the 8-week-old mice. Four weeks later, the Piccolo knockdown mice showed hyperlocomotion in the novel environment and impaired acoustic prepulse inhibition. These observations suggest that dysfunction of Piccolo in the amygdala associates with the behavioral abnormality in schizophrenia. The investigation of the cognitive function and depressive behaviors is necessary in the Piccolo knockdown mice to evaluate as the novel animal model for schizophrenia.		SY21-4 The future prospect on postmortem brain research; from the point of view of similarity and dissimilarity between blood and brain 死後脳を用いて検証したいこと；血液と脳の類似と相違 Numata Shusuke（沼田周助） Department of Psychiatry, Graduate School of Biomedical Sciences, Tokushima University We have used blood samples in our studies because of easy acquisition before, during, and after treatment. To date, we have conducted mRNA expression, DNA methylation, and metabolic profilings of peripheral blood to gain further insight into the molecular mechanisms underlying psychiatric disorders and identify biomarkers for the diagnosis of psychiatric disorders (Kinoshita et al. 2013, Numata et al. 2015, Watanabe et al. 2015, Umehara et al. 2017). While some studies indicate that blood shares significant similarities with CNS tissues in gene expression and DNA methylation (Sullivan et al. 2006, Rollins et al. 2010, Davies et al. 2012), other studies suggest tissue-specific patterns (Christensen et al. 2009, Hannon E et al. 2015, Marzi et al. 2016). Psychiatric disease is a brain disorder, so it will be essential to confirm our blood findings in the human brain in order to increase our knowledge, although postmortem brain samples are limited resources. In this symposium, I will review our studies using peripheral blood samples, and discuss the importance of brain tissues and brain bank activity in this research area.

SY21-5 The latest findings of postmortem brain research in psychiatric disease 精神疾患死後脳研究の実際 Kunii Yasuto（國井泰人） Department of Psychiatry,Aizu Medical Center, Fukushima Medical University In 2014, the genome-wide association study (GWAS) analysis using a largest sample set of 36,989 subjects with schizophrenia and 113,075 controls specified 108 common genetic variants that altered the risk for onset of schizophrenia and the next generation sequencing (NGS) technologies also identified rare and de novo mutations which were associated with risk of schizophrenia. Despite recent these great advances, the precise molecular mechanisms underlying schizophrenia and other psychiatric diseases have not been clarified. Considering the brain specific genome polymorphism such as transcriptional changes, epigenetic modifications and de novo mutations, using human brain tissue is essential to understand molecular pathophysiology of schizophrenia or bipolar disorders. Since 1997 we have managed the systematic postmortem brain bank on psychiatric diseases specializes in schizophrenia for the first time in Japan in order to understand and cure psychiatric diseases and currently maintains 55 brain tissue resources. Recent several postmortem studies including our ones adopted “genetic neuropathology” and provided unique and insights into underlying genetic and molecular mechanisms of schizophrenia. In this conference, we show the latest findings of postmortem brain research in psychiatric disease focusing on the results of our genetic neuropathology and co-research with other institutes using collected postmortem brain samples. Our studies were approved by the Ethics Committee of Fukushima Medical University and complied with the Declaration of Helsinki. All procedures were carried out with the informed written consent of the next of kin, and conducted anonymously and kept confidential.