理事会企画シンポジウム　「統合失調症の分子病態と治療：原因解明と治療法開発の戦略とは」 Board Members Symposium “Molecular pathophysiology and therapy of schizophrenia: Strategy for elucidation of causality and development of new treatment”
S1-3-2-1 統合失調症の病態解明研究に必要な疾患概念と定義 Concept and definition of schizophrenia necessary for pathophysiology elucidation ○橋本亮太1,2, 大井一高2, 安田由華2, 山森英長2,3, 梅田知美3, 藤本美智子2, 武田雅俊1,2 ○Ryota Hashimoto1,2, Kazutaka Ohi2, Yuka Yasuda2, Hidenaga Yamamori2,3, Satomi Umeda-Yano3, Michiko Fujimoto2, Masatoshi Takeda1,2 大阪大院・連合小児発達・子どものこころ1, 大阪大院・医・精神医学2, 大阪大院・医・神経精神3 Mol Res Cent, United Grad Sch of Child Dev, Osaka Univ, Suita1, Dept Psychiatry, Osaka Univ Grad Sch Med, Suita2, Dept Mol NeuroPsych, Osaka Univ Grad Sch Med, Suita3 Psychiatric disorders, such as schizophrenia, have been frequently taken up by symposiums of The Japanese Society for Neurochemistry. Previous symposiums were focused on approaches from a single molecule or neuronal system, however, there were few symposiums in connection with a disease concept or a definition. The aim of this symposium is to clarify directivity to a cause elucidation or development of new therapy by explaining the concepts and definition of mental disorders using schizophrenia as an example. The causality and pathophysiology of schizophrenia have not been elucidated, however, psychiatrists believes that there must be biological pathophysiology underlining schizophrenia. The reason why psychiatrists believe is that patients of similar clinical symptoms shows similar clinical course. However, psychiatrist also believes that schizophrenia is not a sole disease but a heterogeneous disease, aggregation of many diseases. At present, schizophrenia is defined as a syndrome by a set of clinical symptoms, such as auditory hallucination and delusion, and disturbed social functioning, without status due to physiological effects and general medical conditions. Historically, when a cause is specified by a certain group in syndrome until now, much clearer disease concept of a psychiatric disorder has been attained by removing the group from syndrome and making the certain group independent as a new disease unit. For example, neurosyphilis, which has been diagnosed as schizophrenia because of similar clinical symptom with schizophrenia, was isolated from schizophrenia when syphilis spirochete was discovered in brain. First speaker of this symposium will talk about the concepts and definition of schizophrenia and recent advance of clinical research in this field, and then three speakers will present basic research strategy in schizophrenia using neurochemical methodology.	S1-3-2-2 神経細胞の形態形成と統合失調症 Neural morphogenesis and schizophrenia ○中澤敬信1 ○Takanobu Nakazawa1 東京大学大学院　医学系研究科　神経生理学分野1 Department of Neurophysiology, Graduate School of Medicine, University of Tokyo1 Altered dendritic spine morphology is implicated in the pathogenesis of schizophrenia. Recent genetic studies have identified several schizophrenia-related genes that have definite roles in dendritic spine morphogenesis. I previously identified novel Rho GTPase-activating proteins (RhoGAPs), p250GAP and TCGAP, both of which are enriched in the brain. These proteins constitute a subfamily in the large RhoGAP family of proteins, because, in addition to the RhoGAP domain, they unusually share their PX domain which is involved in surface protein trafficking. Genetic manipulation of p250GAP and TCGAP resulted in abnormal spine morphology and impaired surface protein trafficking, implying their molecular roles in linking intracellular protein trafficking to dendritic spine morphogenesis. I then investigated the possible association between schizophrenia and genetic variation in the p250GAP and TCGAP genes and found that single nucleotide polymorphisms associated with risk for schizophrenia at both the p250GAP and TCGAP gene loci. The allele of the p250GAP gene, which was overrepresented in schizophrenia patients, was associated with higher scores of schizotypal personality traits in mentally healthy subjects. Similarly, the affected allele of the TCGAP gene was associated with reduced brain volume in several regions of schizophrenia patients. Impaired working memory of TCGAP knockout mice was cancelled by chronic treatment with an atypical antipsychotic, clozapine. From these results showing the association between the genetic variation in the p250GAP and TCGAP genes and intermediate phenotypes of schizophrenia, I conclude that the p250GAP/TCGAP family of RhoGAP genes may be a new candidate gene family for susceptibility to schizophrenia.
S1-3-2-3 統合失調症とPACAPシグナル経路 PACAP signaling pathway implicated in schizophrenia ○橋本均1,2 ○Hitoshi Hashimoto1,2 大阪大院・薬・神経薬理1, 大阪大・金沢大・浜松医大・千葉大・福井大　連合小児発達・子どものこころの分子統御機構研究セ2 Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University1, Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University2 Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional neuropeptide acting as both neurotransmitter and neurotrophic factor. There is accumulating and compelling evidence that implicates dysregulation of PACAP-signaling pathway in psychiatric disorders. Our previously developed mice lacking PACAP showed marked behavioral and neurophysiological changes, including novelty-induced hyperlocomotion, deficits in prepulse inhibition, impaired memory retention, depression-like behavior as well as altered responsiveness of the hypothalamic-pituitary-adrenal axis to stress. Most of these abnormalities were reversed by the atypical antipsychotic drug risperidone. Genetic association analysis of schizophrenia in a Japanese population provided evidence that genetic variants of PACAP and PACAP receptor PAC1 genes are associated with schizophrenia. Further, the overrepresented allele of the SNP rs1893154 in schizophrenia was associated with poorer visual memory performance and reduced hippocampal volume. In addition, copy number variations of the PACAP gene as well as the gene for the VPAC2 receptor-a common receptor for PACAP and VIP-have been shown to link to severe mental retardation and increased risk for schizophrenia, respectively. These findings implicate PACAP in psychiatric disorders including schizophrenia and suggest that PACAP-signaling pathway might represent a potential drug target for psychiatric disorders. In this paper, I would like to discuss this possibility by reviewing the studies that highlight the functions of PACAP with respect to psychiatric disorders.	S1-3-2-4 サイトカインによる統合失調症のモデリングと創薬 Animal modeling of schizophrenia with cytokines; its application to drug development ○那波宏之1, 水野誠1 ○Hiroyuki Nawa1, Makoto Mizuno1 新潟大学　脳研究所　分子神経生物1 Dept Mol Neurobiol, Brain Res Inst, Niigata Univ1 Inflammatory cytokines are implicated in the developmental hypothesis of schizophrenia. Our previous postmortem studies also support the neuropathologic implication of the cytokines (EGF, IL-1, and NRG). Based on these findings, we have established rodent models for schizophrenia by subcutaneously administering these cytokines to mouse, rat, and monkey neonates. For example, the rodent model with EGF exhibits various behavioral abnormalities in acoustic startle response, prepulse inhibition, latent learning, social interaction, and sensitivity to psychostimulants, most of which can be ameliorated by atypical antipsychotics. In spite of their ventricular enlargement, its gross learning ability and brain structures appeared to be normal. We aimed at developing a new class of the antipsychotic drugs not acting on D2 using these animal models for schizophrenia. We challenged pregnant mice and/or neonatal rats with cytokines (EGF, IL-1, neuregulin-1) as well as with bacterial lipopolysaccharides (LPS) or by hippocampal lesion. We examined the antipsychotic actions of immunomodulatory agents; ErbB inhibitors, emodin, thalidomide and lenalidomide, which are all known to attenuate or modulate inflammatory cytokine signaling. Subchronic administration of lenalidomide significantly ameliorated deficits of social interaction and prepulse inhibition of EGF-treated rats. In contrast, emodin and ErbB inhibitors only improved PPI deficits. We also observed similar anti-psychotic activities of these agents in the other animal model established with maternal LPS challenge or neonatal hippocampal lesioning as well. However, these drugs themselves did not affect weight gain and locomotor activity, suggesting no apparent side effects. These results suggest that immunomodulatory or anti-inflammatory pathway can be a new class of antipsychotic target for schizophrenia.

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