ポスター発表 (Poster Sessions)

統合失調症 Schizophrenia
P2-2-205 統合失調症における灰白質皮質厚と白質統合性との全脳での病理的関連について Global association of cortical thickness and white matter integrity in the pathology of schizophrenia ○笹本彰彦¹, 宮田淳¹, 久保田学¹, 川田良作¹, 藤本心祐¹, 田中祐輔¹, 挾間雅章¹, 杉原玄一¹, 澤本信克², 福山秀直², 高橋英彦¹, 村井俊哉¹ ○Akihiko Sasamoto¹, Jun Miyata¹, Manabu Kubota¹, Ryosaku Kawada¹, Shinsuke Fujimoto¹, Yusuke Tanaka¹, Masaaki Hazama¹, Genichi Sugihara¹, Nobukatsu Sawamoto², Hidenao Fukuyama², Hidehiko Takahashi¹, Toshiya Murai¹¹ 京都大学医学研究科脳病態生理学講座（精神医学）¹, 京都大学医学研究科附属脳機能総合研究センター² Department of Neuropsychiatry, Graduate School of Medicine, Kyoto University, Japan¹, Human Brain Research Center, Graduate School of Medicine, Kyoto University, Japan² Schizophrenia (Sc) has been considered as a neurodevelopmental disorder. Recent progress of neuroimaging has revealed alterations in the brains of Sc. The alterations include gray matter (GM) volume reductions mainly in the frontal and temporal regions, and lower integrity of white matter (WM) tracts such as the fronto-temporal connections. However, to date, there have been only few studies on the associations of the GM and WM pathologies in Sc. Based on the neurodevelopmental hypothesis of Sc, we assumed that the pathologies of both GM and WM would be associated in Sc. To shed light of this issue, we used multi-modal imaging technique, i.e. 81-direction diffusion tensor imaging (DTI) and T1-weighted 3D magnetic resonance imaging (MRI) to investigate the relationship between indices of global mean cortical thickness of GM and mean fractional anisotropy (FA) in the whole WM tracts common to all subjects in Sc and the age-, gender- and educational-year-matched healthy controls (Hc). Cortical thickness was measured with the surface-based approach, while mean FA was estimated with tract-based spatial statistics (TBSS) on FSL program.We found that the global mean cortical thickness of each hemisphere was significantly thinner in Sc, prominent in frontal, insula, and temporal areas compared with Hc. On the other hand, the mean FA was significantly lower in Sc which were attributable to significant FA decreases in widespread WM tracts in Sc compared to Hc. In Sc group, mean FA was significantly and positively correlated with global mean cortical thicknesses. This correlation remained significant even after controlling demographic variables. On the contrary, the correlation was not significant in Hc group. These findings support the idea that some neurodevelopmental underpinning bridges the pathologies of GM and WM in the disease-specific process of Sc.	P2-2-206 GAD67ヘテロノックアウトマウスの行動解析 Behavioral characterization of heterozygous GAD67 knockout mice ○藤原和之¹, 三輪秀樹^1,3, 三國雅彦², 柳川右千夫^1,3 ○Kazuyuki Fujihara¹, Hideki Miwa^1,3, Masahiko Mikuni², Yuchio Yanagawa^1,3 群馬大学大学院　医学系研究科　遺伝発達行動学¹, 群馬大学大学院　医学系研究科　神経精神医学², 科学技術振興機構 CREST³ Dept. of Genet. and Behavioral Neurosci., Gunma Univ. Grad. Sch. of Med., Maebashi, Japan¹, Dept. of Psychiatry and Neurosci., Gunma Univ. Grad. Sch. of Med., Maebashi, Japan², JST, CREST, Tokyo, Japan³ Glutamate decarboxylase 67 kDa isoform (GAD67) is specifically expressed in GABAergic inhibitory neurons. This enzyme is one of the GABA synthetic enzymes, and also has a crucial role for formation of the oral palate through neuronal activity in the hypoglossal nucleus during developmental period. GAD67(-/-) mice showed cleft palate and died at postnatal day 1 because of insufficiency of sucking. GAD67(+/-) mice survive to adults, but their behavioral phenotype remains largely undetermined. In addition, postmortem brain studies have revealed that GAD67 expression level is decreased in the brains of psychiatric disorders, such as schizophrenia. Some studies using animal models have also suggested that imbalance between excitatory and inhibitory transmission plays an important role in the pathophysiology of psychiatric disorders. Therefore, we attempted to determine the effect of GAD67 reduction on behavioral phenotype. We used only adult male GAD67(+/-) mice for behavioral tests. The body weight and general health conditions were not different between GAD67(+/-) mice and control wild-type littermates. We carried out light/dark transition test, elevated plus maze test, acoustic startle test, prepulse inhibition test, open field test, social interaction test, Y-maze test, forced swim test, and fear conditioning test. The prepulse inhibition is one of the most common phenotype among the schizophrenia-related behaviors in model animals, but there was no significant difference between GAD67(+/-) mice and wild-type littermates. In the other behavioral tests, there were also no differences between two genotypes. These results suggest that only moderate GAD67 reduction in all GABAergic neurons cannot cause psychiatric disorder-related behaviors. In the next step, interaction between GAD67 reduction and environmental factors should be studied in GAD67(+/-) mice because psychiatric disorders are thought to be caused by both genetic and environmental factors.
P2-2-207 マウス発育期隔離飼育によるセロトニン作動性下行性疼痛抑制系の活性化 Isolation rearing-induced activation of the descending serotonergic pain inhibitory system in mice ○吾郷由希夫¹, 堀口直剛¹, 浅田和希¹, 田熊一敞¹, 松田敏夫^1,2 ○Yukio Ago¹, Naotaka Horiguchi¹, Kazuki Asada¹, Kazuhiro Takuma¹, Toshio Matsuda^1,2 大阪大院・薬・薬物治療¹, 5大学連合小児発達² Lab. of Medicinal Pharmacol., Grad. Sch. of Pharmaceut. Sci., Osaka Univ., Suita, Osaka¹, Unit-Grad. Sch. of Child Dev., Osaka Univ., Suita, Osaka² Isolation rearing in rodents causes not only abnormal behaviors which resemble the clinical symptoms of schizophrenia, but also hypoalgesia in thermal nociception models. However, the mechanism of the hypoalgesia is not known. The present study investigated the effect of isolation rearing on acute pain and the descending pain inhibitory pathways in mice. Rearing in isolation for 6 weeks from post-weaning reduced pain sensitivity in the hot plate test and acetic acid-induced writhing test. Isolation rearing also reduced the intraplantar capsaicin-induced licking behavior. Capsaicin increased c-Fos expression, a neuronal activity marker, in the spinal cord and primary somatosensory cortex both in group- and isolation-reared mice, but this effect did not differ between groups. On the other hand, c-Fos expression in the anterior cingulate cortex, periaqueductal gray matter and rostral ventromedial medulla, but not in the spinal cord or somatosensory cortex, was enhanced by isolation rearing. Systemic administration of WAY100635 (serotonin_1A receptor antagonist), but not of ketanserin (serotonin₂ receptor antagonist), prazosin (α₁-adrenoceptor antagonist) or yohimbine (α₂-adrenoceptor antagonist), attenuated isolation rearing-induced hypoalgesia in capsaicin-induced licking behavior. Attenuation of isolation rearing-induced hypoalgesia was also observed following the intrathecal injection of WAY100635. Naloxone, an opioid receptor antagonist, did not affect the hypoalgesia in isolation-reared mice. These findings suggest that isolation rearing causes hypoalgesia in mouse models of acute pain and imply that the spinal serotonin_1A receptor activation probably through descending serotonergic inhibitory pathway is involved in isolation rearing-induced hypoalgesia.	P2-2-208 上皮成長因子過剰発現マウスの神経行動学的な異常;ドパミン代謝への影響 Neurobehavioral Deficits of Epidermal Growth Factor-Overexpressing Transgenic Mice; Impact on Dopamine Metabolism ○江田岳誉¹, 水野誠¹, 外山英和¹那波宏之¹ ○Takeyoshi Eda¹, Makoto Mizuno¹, Hidekazu Sotoyama¹, Siu-Yuen Chan², Hiroyuki Nawa¹ 新潟大学脳研究所分子神経生物学¹ Department of Molecular neurobiology, Brain Research Institute, Niigata University¹, Department of Paediatrics and Adolescent Medicine, the University of Hong Kong, China.² Epidermal growth factor (EGF) is a homologue of neuregulin-1 and implicated in the etiology of schizophrenia. We reported abnormal expression of EGF and EGF receptor in the brain tissues and peripheral blood of schizophrenic patients. Our preceding animal studies indicate that EGF injections to neonatal and adult rats both induce neurobehavioral deficits relevant to schizophrenia, although we did not evaluate the indirect influence of anti-EGF antibody production in these animals. We analyzed transgenic mice carrying the transgene of mouse EGF cDNA. As compared to control littermates, heterozygous EGF transgenic mice had an increase in EGF receptor signaling and showed significant decreases in prepulse inhibition and context-dependent fear learning, but no changes in locomotor behaviors and sound startle responses. In addition, these transgenic mice exhibited higher behavioral sensitivity to the repeated injections of cocaine (20mg/kg/day, 5days, i.p.). There were neurochemical alterations of monoamine contents [i.e., tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), and catechol-o-methyltransferase (COMT)] in various brain regions of EGF transgenic mice. However no apparent neuropathological signs in their brain. These findings support the preceding results from animal models established with EGF administration; aberrant hyper-signals of EGF have significant impact on mouse behavioral traits and dopamine metabolism.
P2-2-209 統合失調症を併発した22q11.2欠失症候群患者由来のiPS細胞を用いたトランスクリプトーム解析 Transcriptome analyses of human induced pluripotent stem cells from 22q11.2 deletion syndrome patients with schizophrenia ○豊島学¹, 岡田洋平³, 赤松和土³, 糸川昌成², 岡野栄之³, 吉川武男¹ ○Manabu Toyoshima¹, Yohei Okada³, Wado Akamatsu³, Masanari Itokawa², Hideyuki Okano³, Takeo Yoshikawa¹ 理化学研究所　脳科学総合研究センター　分子精神科学研究チーム¹, 東京都医学総合研究所　統合失調症・うつ病プロジェクト², 慶應義塾大学　医学部　生理学教室³ Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Japan¹, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Japan², Department of Physiology, Keio University School of Medicine, Japan³ Schizophrenia is a debilitating mental illness, with a prevalence of approximately 1% worldwide, making it a relatively common disease. Although the exact etiology is unknown, the genetic pathology is thought to consist of numerous weak, risk-conferring genomic variations and/or rare, large effect variations. An example of the latter is copy number variants or CNVs, typified by the 22q11.2 deletion syndrome (22q11.2DS; also known as the velocardiofacial syndrome or DiGeorge syndrome). To elucidate the effect of the genomic deletion defect on schizophrenia, we established human induced pluripotent stem cells (hiPSCs) from 22q11.2 DS patient with schizophrenia. We established iPS cell lines from patients with schizophrenia who also carry 22q11.2 microdeletion, and from controls. iPS cells generated from fibroblast cells using four transcription factor gene (Oct3/4, Sox2, Klf4, c-Myc). We differentiated those cells to Neurosphere (NS), and performed transcriptome analyses (mRNA, miRNA) using a next generation sequencer and commercially available chips. In this case, 22q11.2DS patient has 2.6 Mb deletion region including 56 genes. Several gene expressions were halved in iPSC and NS. DGCR8 expression was detected in iPSC and Neurospheres. But DGCR8 levels were halved in NS alone. DGCR8 has a role in miRNA processing. We particularly focused on the signature of miRNA expression profiles. miRNA expression profiles was changed in NS derived from 22q11.2 DS patients. Expression of miR-9, miR-124, let-7 were decreased in NS derived from patients alone. These miRNA promote neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. It is suggested that NS derived from patients were low neuronal differentiation.	P2-2-210 統合失調症における血液中L-セリン合成酵素mRNA発現量の検討 mRNA expression of L-serine synthesis enzyme in the peripheral blood of patients with schizophrenia ○尾関祐二^1,2, 関根正恵³, 藤井久彌子¹, 渡邊崇¹, 高野有美子¹, 岡安寛明¹, 篠崎隆央¹, 青木顕子¹, 青木秀明⁴, 森玄房⁵, 秋山一文⁶, 本間浩³, 下田和孝¹ ○Yuji Ozeki^1,2, Masae Sekine³, Kumiko Fujii¹, Takashi Watanabe¹, Yumiko Takano¹, Hiroaki Okayasu¹, Takahiro Shinozaki¹, Akiko Aoki¹, Hideaki Aoki⁴, Harunobu Mori⁵, Kazufumi Akiyama⁶, Hiroshi Homma³³, Kazutaka Shimoda¹ 獨協医科大学精神神経医学¹, 国立精神・神経医療研究センター　疾病研究第三部², 北里大学薬学部生体分子解析学教室³, 大澤台病院⁴, 森病院⁵, 獨協医科大学　精神生物学講座⁶ Dept Psychiatry, Dokkyo Med Univ, Mibu¹, Dept Mental Dis Res, NIN, NCNP, Tokyo², Lab Biomol Sci, Dept Pharmaceutical Life Sci, Kitasato Univ, Tokyo³, Osawadai Hosp⁴, Mori Hosp⁵, Dept Bio Psychiat Neurosci, Dokkyo Med Univ, Mibu⁶ Purpose: We previously reported a case of schizophrenia with low serum L-serine concentration due to disturbances in the L-serine synthesis pathway. The purpose of this study is to compare mRNA expression of peripheral blood enzymes that are essential for L-serine synthesis, such as 3-phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and 3-phosphoserine phosphatase (PSP) between sporadic cases of schizophrenia and healthy controls. Methods: Seventy-two patients with schizophrenia (mean age, 49.3 years; standard deviation (SD), 12.0) and 51 healthy subjects (mean age, 45.9 years; SD, 12.6) participated in this study. mRNA were extracted from the peripheral blood. Quantitative real-time polymerase chain reaction was performed. The Mann-Whitney U-test was performed to compare mRNA expression between patients with schizophrenia and healthy controls. This study was approved by the Institutional Review Boards of Dokkyo Medical University. Results: Relative mRNA expression of PSAT1 and PSP compared with that of either glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or beta-actin was significantly decreased in patients with schizophrenia (both, p<0.001). Furthermore, relative mRNA expression of PHGDH compared with that of GAPDH was significantly decreased in patients with schizophrenia (p<0.01). However, relative mRNA expression of PHGDH in comparison with that of beta-actin was not significantly decreased (p = 0.024) Conclusions: These results may indicate the impairment of the L-serine synthesis pathway in patients with schizophrenia. However, there are some limitations. Patients with schizophrenia in our study were prescribed neuroleptics. Furthermore, there is no guarantee that mRNA expression in whole blood will reflect that in the central nervous system. Further investigations are required to confirm the role of the L-serine synthesis pathway in the etiology of schizophrenia.
P2-2-211 統合失調症における全ゲノム関連メガ解析による遺伝子多型の脳構造への影響；包括的VBM解析 Impacts of the genome-wide association mega-analysis supported variants on brain morphology in schizophrenia; a comprehensive VBM analysis ○大井一高^1,2, 橋本亮太^1,3, 安田由華¹, 根本清貴⁴, 大西隆^5,6, 藤本美智子¹, 山森英長^1,7, 梅田知美⁷, 岩瀬真生¹, 数井裕光¹, 武田雅俊^1,3 ○Kazutaka Ohi^1,2, Ryota Hashimoto^1,3, Yuka Yasuda¹, Kiyotaka Nemoto⁴, Takashi Ohnishi^5,6, Michiko Fujimoto¹, Hidenaga Yamamori^1,7, Satomi Umeda⁷, Masao Iwase¹, Hiroaki Kazui¹, Masatoshi Takeda^1,3 大阪大学大学院医学系研究科精神医学教室¹, 国立病院機構やまと精神医療センター², 大阪大学大学院連合小児発達学研究科附属子どものこころの分子統御機構研究センター³, 筑波大学人間総合科学研究科　精神病態医学⁴, 国立精神・神経センター精神保健研究所心身医学研究部⁵, ヤンセンファーマ株式会社サイエンティフィックアフェアーズCNSサイエンス部⁶, 大阪大学大学院医学系研究科分子精神神経学（大日本住友製薬）寄付講座⁷ Dept Psychiatry, Osaka Univ Gra Sch Med¹, National Hospital Organization, Yamato Mental-Medical Center², Mol Res Center for Children's Mental Development, United Gra Sch Child Development, Osaka Univ³, Dept Neuropsychiatry, Insti Clin Med, Univ Tsukuba⁴, Dept Psychosomatic Res, National Institute of Mental Health, National Center of Neurology and Psychiatry⁵, CNS Science Dept, Scientific Affairs Division, Janssen Pharmaceutical K.K.⁶, Dept Mol Neuropsychiatry, Osaka Univ Gra Sch Med⁷ Background: A mega-analysis combining genome-wide association study data and the replication analysis (N=51,695) have yielded genome-wide significant associations of schizophrenia with eight SNPs [rs1625579 (MIR137), rs17662626 (PCGEM1), rs2021722 (TRIM26), rs10503253 (CSMD1), rs7004633 (MMP16), rs7914558 (CNNM2), rs11191580 (NT5C2) and rs12966547 (CCDC68)] from the seven loci (1p21.3, 2q32.3, 8p23.2, 8q21.3, 10q24.32-q24.33, 6p21.32-p22.1 and 18q21.2). However, the role of these SNPs on brain structures remains unclear. Methods: The genotype effects of these eight SNPs on gray matter volumes between major-allele homozygotes and minor-allele carriers were investigated using magnetic resonance imaging (MRI) study with a voxel-based morphometry (VBM) technique separately in 170 Japanese patients with schizophrenia and 437 healthy subjects. Results: In patients with schizophrenia, individuals with the risk G/G genotype of rs7914558 in the CNNM2 gene had a smaller volume in the left inferior frontal gyrus than carriers of the non-risk allele (FWE-corrected p=0.045). In controls, there was no significant effect of the genotype on the region (FWE-corrected p>0.05). Although several significant genotype effects of other SNPs on brain volumes were observed for the patients or controls (uncorrected p<0.001), these effects did not survive after the FWE-correction for multiple tests (FWE-corrected p>0.05). Conclusions: The rs7914558 within an intron of the CNNM2 gene is the second strongest genome-wide associated SNP. Our findings suggest that the genome-wide associated genetic variant could be related to brain morphology in patients with schizophrenia.	P2-2-212 発達期の脂肪酸欠乏食投与による精神疾患関連遺伝子の発現変化 Regulation of psychiatric disorder related genes by lack of PUFA during developmental stage in mice ○前川素子¹, 木村哲也², 浜崎景³, 渡辺明子¹, 岩山佳美¹, 大羽尚子¹, 久野泰子¹, 文東美紀⁴, 岩本和也⁴, 大西哲生¹, 豊島学¹, 大隅典子⁵, 加藤忠史⁶, 高島明彦², 吉川武男¹ ○Motoko Maekawa¹, Tetsuya Kimura², Kei Hamazaki³, Akiko Watanabe¹, Yoshimi Iwayama¹, Hisako Ohba¹, Yasuko Hisano¹, Miki Bundo⁴, Kazuya Iwamoto⁴, Tetsuo Ohnishi¹, Manabu Toyoshima¹, Noriko Osumi⁵⁵, Tadafumi Kato⁶, Akihiko Takashima², Takeo Yoshikawa¹ 理研・BSI・分子精神科学¹, 国立長寿医療研究センター・分子基盤部², 富山大学・公衆衛生³, 東京大学・院医・分子精神医学⁴, 東北大学・院医・発生発達神経科学⁵, 理研・BSI・精神疾患動態⁶ Lab for Molecular Psychiatry, RIKEN BSI, Saitama, Japan¹, National Center for Geriatrics and Gerontology, Aichi, Japan², University of Toyama, Toyama, Japan³, University of Tokyo, Tokyo, Japan⁴, Tohoku University, Sendai, Japan⁵, Lab for Molecular Dynamics of Mental Disorders, RIKEN BSI, Saitama, Japan⁶ Large epidemiological data show that when pregnant mothers experienced malnutrition or famine, the psychosis risk of offspring was significantly increased. On the other hand, the abnormalities in polyunsaturated fatty acids (PUFAs) metabolism are reported to be relevant across psychiatric illnesses. These facts suggest that the lack of PUFA during developmental stage may cause vulnerability of mental disorders in later life stage.To address this issue, we raised mice with AA (arachidonic acid) / DHA (docosahexaenoic acid)-deficient diet during developmental stage. The mice fed AA/DHA-deficient diet showed some behavioral changes, neuronal activity changes in the medial prefrontal cortex and downregulation of genes reported in schizophrenia/bipolar disorder postmortem brains (e.g. those for oligodendrocytes and GABAergic genes). These results provide innovative clues for the pathophysiology of mental disorders, demonstrating an important role of PUFAs during neurodevelopement. We are now studying regulatory mechanism of alteration of these gene expressions in terms of epigenetic modifications of transcription factors.
P2-2-213 統合失調症患者死後脳におけるGWASで報告された統合失調症関連遺伝子の発現解析 Expression analysis of the genes identified by GWAS in postmortem brain tissues from schizophrenia ○山森英長^1,2, 橋本亮太^2,3, 梅田知美¹安田由華², 大井一高², 藤本美智子², 伊藤彰¹, 武田雅俊² ○Hidenaga Yamamori^1,2, Ryota Hashimoto^2,3, Satomi Umeda-Yano¹, Cyndi Shannon Weickert⁴, Yuka Yasuda², Kazutaka Ohi², Michiko Fujimoto², Akira Ito¹, Masatoshi Takeda² 大阪大学大学院　医学系研究科　分子精神神経学（大日本住友製薬）寄附講座¹, 大阪大学大学院　医学系研究科　精神医学教室², 大阪大学大学院　連合小児発達学研究科附属子どものこころの分子統御機構研究センター³ Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Osaka, Japan¹, Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan², Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan³, Schizophrenia Research Institute, University of New South Wales, Neuroscience Research Australia, Sydney, Australia⁴ Many gene expression studies have been performed using postmortem brain tissues from Schizophrenia (SZ). However, only a few expression studies of the genes identified by genome-wide association study (GWAS) were reported so far. We have measured the expression of the genes identified by GWAS (ZNF804A, OPCML, RPGRIP1L, NRGN or TCF4) in postmortem brain tissues of schizophrenic patients and controls from two separate sets of samples (Australian Tissue Resource Center and Stanley Medical Research Institute). We also determined if single-nucleotide polymorphisms (SNPs) identified by GWAS were related to change gene expression in the prefrontal cortex. No difference was observed in the mRNA levels of ZNF804A, OPCML, RPGRIP1L, NRGN or TCF4 between SZ and controls from the Australian Tissue Resource Center samples. The lack of mRNA change for these five transcripts was also found in the brain samples from the Stanley Medical Research Institute. In addition, no relationship between SNPs associated with SZ by GWAS and the corresponding gene expression was observed in either set of samples. Our results suggest that major changes in transcript levels for 5 candidate genes identified by GWAS may not exist in adult patients with SZ. The lack of linkage between risk gene polymorphism and expression levels of their major transcripts suggests that control of pan mRNA levels may not be a prominent mechanism by which genes identified by GWAS contribute to the pathophysiology of SZ. Now we are measuring the mRNA expression of CSMD1, C10orf26 and CACNA1C, the genes newly identified by Mega-GWAS. Further studies are needed to examine how the genes identified by GWAS contribute to the pathophysiology of SZ.	P2-2-214 新規神経栄養因子様化合物 T-817MA はPDGFR-β ノックアウトマウスの陰性症状を改善する T-817MA, a novel neurotrophic agent, ameliorated negative symptoms of PDGFR-β KO mice ○中村友也¹, 堀悦郎¹, 高村雄策¹, 寺澤彩乃¹, 濱島丈³, 石井陽子³, 松島貴子³, 小野武年², 笹原正清³, 西条寿夫¹ ○Tomoya Nakamura¹, Etsuro Hori¹, Yusaku Takamura¹, Ayano Terasawa¹, Takeru Hamashima³, Youko Ishi³, Takako Matsushima³, Taketoshi Ono², Masakiyo Sasahara³, Hisao Nishijo¹ 富山大学大学院　医学薬学研究部　システム情動科学¹, 富山大学　神経・整復学講座², 富山大学　病態病理学³ Dept System emotional Sci, Univ of Toyama, Toyama¹, Dept Judo Neurophysiotherapy, Univ of Toyama, Toyama², Dept Pathology, Univ of Toyama, Toyama³ Dysfunction of parvalbumin-positive (GABAergic) neurons suggested to be a final common pathway to schizophrenia and autism with abnormalities of gamma oscillation between 30-80Hz. Since gamma oscillation underlies various cognitive functions, gamma oscillatory abnormality could induce negative symptoms of autism and schizophrenia; cognitive deficits and reduction of social interaction, emotion, and motivation. Therefore, parvalbumin-positive neurons are important targets for pharmacological therapy. However, there have been no effective drugs for parvalbumin-positive neurons. In the present study, we investigated effects of a newly synthesized drug, T-817MA, which displays neuroprotective and neurotrophic effects, on parvalbumin-positive neurons. T-817MA was administered to Platelet-derived growth factor (PDGF) receptor-β KO mice. Previous our behavioral study indicated that PDGFR-β KO mice showed deficits in social interaction, prepulse inhibition (PPI), fear conditioning, spatial memory, and also forced swimming. Furthermore, an immunohistochemical analysis indicated that the number of parvalbumin-positive (GABAergic) neurons was reduced in the PDGFR-β KO mice. Consistent with this finding, auditory event-related gamma oscillation in the frontal cortex was reduced in the PDGFR-β KO mice. However, oral administration of T817-MA ameliorated not only reduction in number of parvalbumin-positive neurons and gamma oscillation, but also behavioral deficits in PDGFR-β KO mice. These findings suggest that T817-MA might exert neuroprotective and/or neurotrophic effects on parvalbumin-positive neurons, which ameliorated gamma oscillation. T-817MA may be a new drug candidate for negative symptoms of schizophrenia and autism through its effects on parvalbumin-positive neurons.
P2-2-215 統合失調症における安静時前頭ネットワークの変化 -resting state fMRI 研究 Altered frontal brain resting state networks in schizophrenia -A resting state fMRI study ○福永雅喜¹, 橋本亮太^2,3, 渡邊嘉之⁴, 大井一高³, 山森英長^3,5, 藤本美智子³, 安田由華³, 武田雅俊³ ○Masaki Fukunaga¹, Ryota Hashimoto^2,3, Yoshiyuki Watanabe⁴, Kazutaka Ohi³, Hidenaga Yamamori^3,5, Michiko Fujimoto³, Yuka Yasuda³, Masatoshi Takeda³ 大阪大学免疫学フロンティア研究センター¹, 大阪大学大学院大阪大学・金沢大学・浜松医科大学・千葉大学・福井大学連合小児発達学研究科附属子どものこころの分子統御機構研究センター疾患関連分子解析部門², 大阪大学大学院医学系研究科情報統合医学講座精神医学教室³, 大阪大学大学院医学系研究科放射線統合医学講座放射線医学講座⁴, 大阪大学大学院医学系研究科分子精神神経学 (大日本住友製薬) 寄附講座⁵ Biofunc img, IFReC, Osaka Univ, Osaka, Japan¹, Mol Res Cen for Child Mental Dev, United Grad Sch of Child Dev, Osaka Univ, Osaka, Japan², Dept of Psych, Osaka Univ Grad Sch of Med, Osaka, Japan³, Dept of Radiol, Osaka Univ Grad Sch of Med, Osaka, Japan⁴, Dept of Mol Neuropsych, Osaka Univ Grad Sch of Med, Osaka, Japan⁵ Schizophrenia is one of major mental disorders with poor prognosis and that has a relatively high impact on life. However currently there are no imaging biomarkers for schizophrenia available in clinically applicable situations. The purpose of this study was to investigate alteration of resting state brain networks of patients with schizophrenia compared with healthy controls using fMRI.Fourtytwo patients with schizophrenia (SZ: male/female: 21/21, duration of illness: 12.1+10.4y., age of onset: 22.7+2.1y.o.) and age-, gender-matched healthy controls (HC) participated in this study after providing informed consent. MRI scans were performed on a 3T scanner. During 5 minutes fMRI scan, subjects were instructed to close their eyes, be relaxed and stay awake. In order to detect and characterize brain network activity, we applied group level spatial independent component analysis (ICA) to patients and controls separately, using MELODIC 3.1 (FSL4.1) and dual regression extension. The number of extracted components was limited to 20. After ICA, inter-group similarity of ICs was evaluated by determining their spatial correlation. Both SZ and HC are characterized by a large number of ICs covering large part of gray matter regions. These ICs showed apparent functionally related regions (visual, sensory-motor, auditory and its associate areas). Most of the extracted ICs in both groups were highly spatially correlated (r ≥ 0.4) and well resembled for its anatomical location and extent. We found 18 ICs that showed a high spatial consistency across groups. Remaining ICs (r < 0.4, unmatched between groups) were found at medial frontal - anterior cingulate in only SZ and DLPFC - posterior cingulate, orbitofrontal - caudate/putamen - cerebellum in only HC. Interestingly, default mode network (DMN) in SZ is well remained and corresponded with HC. These results suggest that resting state activity in frontal brain is more vulnerable than DMN.	P2-2-216 Voxel-based morphometryを応用した統合失調症補助診断ソフトの開発 Developing a computer aided diagnosis tool of schizophrenia using voxel-based morphometry ○根本清貴¹, 山下典生², 大西隆³, 山末英典⁴, 八幡憲明⁴, 高橋努⁵, 福永雅喜⁶, 大井一高⁷, 橋本亮太^7,8, 鈴木道雄⁵, 笠井清登⁴, 朝田隆¹ ○Kiyotaka Nemoto¹, Fumio Yamashita², Takashi Ohnishi³, Hidenori Yamasue⁴, Noriaki Yahata⁴, Tsutomu Takahashi⁵, Masaki Fukunaga⁶, Kazutaka Ohi⁷, Ryota Hashimoto^7,8, Michio Suzuki⁵, Kiyoto Kasai⁴, Takashi Asada¹¹ 筑波大・医・精神医学¹, 岩手医・超高磁場MRI診断・病態研究², ヤンセンファーマ・CNS部³, 東大・医・精神医学⁴, 富山大・医・精神医学⁵, 大阪大・免疫学フロンティア研究センター⁶, 大阪大・医・精神医学⁷, 大阪大・金沢大・浜松医大・千葉大・福井大連合小児発達学研究科・子どものこころの分子統御機構研究センター⁸ Dept Psychiatry, Univ of Tsukuba¹, Div MRI, Iwate Med Univ², CNS Dept, Janssen³, Dept Psychiatry, Univ of Tokyo⁴, Dept Psychiatry, Univ of Toyama⁵, Immun Res Center, Osaka Univ⁶, Dept Psychiatry, Osaka Univ⁷, Mental Development, Osaka Univ⁸ Background: Though accumulating evidence reveal that patients with schizophrenia show volume reduction in superior temporal gyrus or medial temporal regions, little efforts have been made to apply these findings to clinical settings for diagnosis of schizophrenia. In this study, we developed a computer aided diagnosis tool of schizophrenia using voxel-based morphometry and evaluated its accuracy. Methods: Subjects are 129 schizophrenia patients and 167 control subjects in their twenties or thirties from three different institutes. A three-dimensional T1-weighted MRI dataset from institute A (35 patients and 73 controls) was used to build regions of interest (ROIs) for diagnosis of schizophrenia. Other MRI datasets from institute B (30 patients and 30 controls) and institute C (64 patients and 64 controls) were used for the discrimination analysis. First, a two sample t-test was performed using grey matter (GM) images derived from dataset A and we defined ROIs where patients showed volume reduction. We also calculated the mean and standard deviation maps of GM images from control subjects to generate Z-score maps. Then, we developed a Matlab-based program which employs VBM8 algorithm segmentation and calculates GM Z-score map of each subject automatically. We extracted a mean Z-score in ROIs of each subject and entered in discrimination analysis. Results: The two sample t-test showed GM volume reduction of schizophrenia in several regions such as bilateral superior temporal gyri, anterior cingulate cortices, and inferior frontal gyri. The accuracy of diagnosis gained from the discrimination analysis using dataset from institute B and C was 76.7% and 68.8%, respectively. Conclusions: With a simple one index, i.e., a mean Z-score within ROIs, we could discriminate schizophrenia from control subjects with moderate accuracy. Our results indicate structural MRI could be a diagnostic means for schizophrenia even in clinical settings.
P2-2-217 カルボニルストレス性統合失調症の研究 Research on schizophrenia associated with carbonyl stress ○糸川昌成^1,2, 新井誠¹, 宮下光弘¹, 市川智恵¹, 鳥海和也¹, 小堀晶子¹, 宮田敏男² ○Masanari Itokawa^1,2, Makoto Arai¹, Mitsuhiro Miyashita¹, Tomoe Ichikawa¹, Kazuya Toriumi¹, Akiko Kobori¹, Toshio Miyata² 東京都医学総合研究所　統合失調症・うつ病プロジェクト¹, 東北大学² Project for Schizophrenia and Aggective Disorders Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan¹, Tohoku University, Sendai, Japan² Main objective; Schizophrenia is a debilitating and complex mental disorder with a prevalence of approximately 1% worldwide. Its pathophysiology remains unclear, despite massive research into it. Biochemical and pharmacological studies using human samples and animal models suggest that oxidative/carbonyl stress contributes to the pathophysiology of schizophrenia. Oxidative stress is a central mediator of advanced glycation end product (AGE) formation, and pyridoxamine is known to detoxify reactive carbonyl compounds (RCOs) via carbonyl-amine chemistry. Strategy and methods; Patients with schizophrenia and control subjects were recruited for biochemical measurements. Deep resequencing of GLO1 derived from peripheral blood or postmortem brain tissue was performed. Phase II trial of schizophrenia using pyridoxamine was done. Main results and conclusion; A novel frameshifted mutation was found in a schizophrenia of a multiple affected family. Expression levels of mRNA and protein of GLO1 decreased by 50% of control. Plasma pentosidine was increased by 3.7 fold and pyridoxal was lower by 20% compared to controls. Biochemical analyses of 45 schizophrenia and 61 controls revealed significant high serum pentosidine and low pyridoxal in patients compared to controls. Pentosidine level was significantly correlated with symptom severity in schizophrenia showing carbonyl stress. Mice lacking GLO1 gene yielded vulnerability of carbonyl stress in brain compared to peripheral and showed regional difference of pentosidine levels in brain. Our findings suggest that GLO1 deficits and carbonyl stress are linked to the development of a certain subtype of schizophrenia. Elevated plasma pentosidine and concomitant low vitB6 levels could be the most cogent and easily measurable 'biomarkers' in schizophrenia, and should be helpful for classifying heterogeneous types of schizophrenia on the basis of their biological causes.

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