統合失調症 Schizophrenia
P3-2-180 脱負荷時の手の動きと筋電図測定による予測に基づく運動制御の個人差の評価 Individual differences in prediction-based motor control assessed in unloading task by measuring hand movements and electromyogram ○菊池ゆひ1, 濱直人2, 若林優衣1, 熊切幸乃1, 米田貢1, 小池康晴3, 少作隆子1 ○Yui Kikuchi1, Naoto Hama2, Yui Wakabayashi1, Yukino Kumakiri1, Mitsugu Yoneda1, Yasuharu Koike3, Takako Ohno-Shosaku1 金沢大学医薬保健研究域・保健・リハビリ1, 東京工業大学　情報工学科2, 東京工業大学　ソリューション研究機構3 Fac. Health Sci. Kanazawa Univ., Kanazawa, Japan1, Tokyo Tech., Yokohama, Japan2, P&I Lab, Tokyo Tech., Yokohama, Japan3 We previously reported that dysfunction of prediction-based motor control in psychiatric patients can be assessed in simple weight unloading task by using accelerometer. In that study, we observed three patterns (A-C) of hand movements; the peak velocity was smaller (A), almost equal (B), and larger (C) in predictable condition than in unpredictable condition, only the first two (A, B) being observed in normal subjects. These different patterns might be caused by (1) the difference in onset of muscle activity change or (2) the difference in tonic muscle activity. The purpose of this study was to distinguish between these two possibilities, by simultaneously measuring hand movements and surface electromyogram (EMG) in normal subjects. To monitor the timing of unloading accurately, we used the Space Interface Device for Artificial Reality (SPIDAR), which consists of four motors and strings attached to a ball-shaped grip. A force of 3.92 N was vertically applied (loading) to the right hand of a subject, and then removed (unloading). Loading or unloading was started when the subject (predictable condition) or examiner (unpredictable condition) pressed the start key. A pair of loading and unloading was repeated 20 times in each condition. Vertical movements of the hand were measured by using SPIDAR and accelerometer. EMG was monitored from flexor carpi radialis, flexor carpi ulnaris and extensor carpi radialis. In unloading task, we observed two patterns (A, B) of hand movements as reported previously. In pattern A, but not pattern B, EMG activity change was observed earlier in the predictable condition, compared to unpredictable condition. The basal EMG activity was not different between these two conditions in both patterns. These data show that the attenuation of hand movement is caused by the prediction-based earlier onset of motor response, and that individual differences in prediction-based motor control can be assessed in simple unloading task.	P3-2-181 脳組織pHの変動による発現プロファイルへの影響 Postmortem brain pH have significant impact on gene expression profiles ○兪志前1,4, 小野千晶1,4, 国井泰人3, 和田明3, 松本純也3, 日野瑞城3, 池本桂子3, 丹羽真一3, 富田博秋1,2,4 ○Zhiqian Yu1,4, Chiaki Ono1,4, Yasuto Kunii3, Akira Wada3, Junya Mastumoto3, Mizuki Hino3, Keiko Ikemoto3, Shinichi Niwa3, Hiroaki Tomita1,2,4 東北大学　災害科学国際研究所　災害精神医学1, 東北大学　東北メディカル・メガバンク機構2, 福島県立医科大学 神経精神医学講座3, 東北大学　医学系研究科4 Department of Disaster Psychiatry, International Research Institute for Disaster Science, Tohoku University, Japan1, Tohoku Medical Megabank Organization, Tohoku University, Japan2, Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Japan3, Graduate School of Medicine, Tohoku University, Japan4 Objective: Molecular research into psychiatric postmortem human tissue has been conducted in the past decade. Microarray has been a major technique for detecting differential RNA expression, which can be significantly influenced by postmortem tissue pH and RNA integrity. So far, measurements of tissue pH and RNA integrity are initial procedure to evaluate RNA quality for molecular studies. The aim of this study was to determine gene expression profiles correspond to tissue pH and RNA integrity, and find a way to evaluate RNA quality based on gene expression profile. Method: Each of postmortem brain tissues (n=13) was divided evenly into 2 pieces. One piece of tissue (20 mg) was homogenized in DNase-free water (100 μl; pH 6.4) by measuring pH on Twin pH-B212 pH meter (HORIBA). Total RNA was extracted from another piece of tissue. RNA integrity was evaluated with Agilent BioAnalyzer 2100 as RNA integrity number (RIN). RNA was applied to gene expression analysis using Illumina microarray system. Result: Tissue pH was significantly correlated with tissue RIN. Expressions of large number of genes were affected by reduction of tissue pH and RIN. Mitochondria-related gene expressions were strongly associated with pH rather than RIN, whereas transport-related genes were associated with RIN. Conclusion: The method for measuring tissue pH using a small amount of postmortem tissue was established in this study. Gene expression profiles correlated to pH and RIN will be useful to evaluate RNA quality control.
P3-2-182 Schnurri-2 マウスで見られる精神疾患の中間表現型としての未成熟歯状回は成育後に出現する "Immature dentate gyrus", a candidate endophenotype for psychotic disorders, emerges after adolescence in Schnurri-2 KO mice ○高雄啓三1,2,3, 萩原英雄2,3, 大平耕司2,3, 昌子浩孝2,3, 服部聡子2,3, 小清水久嗣2,3, 梅森十三2,3, 高木豪4,5, 石井俊輔5, 宮川剛1,2,3 ○Keizo Takao1,2,3, Hideo Hagihara2,3, Koji Ohira2,3, Hirotaka Shoji2,3, Satoko Hattori2,3, Hisatsugu Koshimizu2,3, Juzoh Umemori2,3, Tsuyoshi Takagi4,5, Shunsuke Ishii5, Tsuyoshi Miyakawa1,2,3 自然科学研究機構 生理学研究所 行動・代謝分子解析センター 行動様式解析室1, 総合医科学研究所 藤田保健衛生大学2, 理化学研究所4, 愛知県心身障害者コロニー 発達障害研究所5 Section of Behavior Patterns, NIPS, Okazaki1, ICMS, Fujita Hlth. Univ., Toyoake2, JST CREST, Kawaguchi3, RIKEN, Tsukuba4, Instit. for Dev. Res., Aichi Human Service Ctr., Kasugai5 Schnurri-2 (Shn-2), an NF-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes that have been shown to harbor common variant single nucleotide polymorphisms associated with schizophrenia. Previously, we reported that Shn-2 knockout (KO) mice display abnormal behaviors related to schizophrenia and their brains demonstrate numerous schizophrenia-related phenotypes, including molecular changes remarkably similar to those of schizophrenia patients, and pseudo immaturity of the dentate gyrus (DG) that we termed "immature dentate gyrus (iDG)". However, it is unclear whether iDG phenotype is due to a maturation failure or by a reversal of maturation status ("de-maturation"). Here, we examined brains from Shn-2 KO mice and their wild type littermates at young (two weeks old), and young adult (one month old) age. There were no obvious differences in the expressions of Calbindin (CB), a mature neuron marker, and Calretinin (CR), a marker for immature neuron, between genotypes at young age, suggesting that the DG of Shn-2 KO mice develops normally at this age. The CB expression of the controls at young adult age was greater than that of young age. On the contrary, in Shn-2 KO mice, the CB expression at young adult age was lower than that of young age. The controls at young adult age showed a decreased CR expression compared to the young, whereas the mutants did not. Moreover, working memory deficit in Shn-2 KO mice was not seen at young age, but at young adult age. These results indicate that iDG in Shn-2 KO mice emerges as a result of neuronal de-maturation around or after weaning, which is consistent with the fact that onset of schizophrenia is typically after adolescence. Our data suggest that preventing the de-maturation of the DG neurons may be beneficial to the prevention of schizophrenia.	P3-2-183 覚醒剤過感受性ラット扁桃体での恐怖条件刺激によるドパミン過剰放出に対する抗精神病薬および気分安定薬の効果比較 Differential effects of mood-stabilizer and antipsychotic drugs on excessive dopamine release in the amygdala in response to conditioned fear stress: An in vivo microdialysis study in methamphetamine-sensitized rats ○村岡寛之1, 稲田健1, 河野仁彦1, 河野敬明1, 河西亜希子1, 押淵英弘1, 石郷岡純1 ○Hiroyuki Muraoka1, Ken Inada1, Masahiko Kawano1, Takaaki Kawano1, Akiko Kasai1, Hidehiro Oshibuchi1, Jun Ishigooka1 東京女子医科大学精神科1 Dept of Psychiatry Tokyo Women's Medical University. Tokyo1 Patients with schizophrenia may exhibit emotional hypersensitivity; therefore, it is meaningful to study dopamine dynamics in the amygdala. In our series of studies, we found that dopamine release in the amygdala was significantly increased in methamphetamine (MAP)-sensitized rats compared to control animals during a conditioned fear stress paradigm. Excessive dopamine release is considered a biochemical marker of vulnerability to psychosis, and it is known that antipsychotic drugs antagonize dopamine signaling in the mesolimbic system. However, it is unclear how antipsychotic drugs affect amygdalar function. In contrast, mood-stabilizing drugs are used for augmentation therapy of schizophrenia and other emotional disorders, but there is no biochemical evidence that they exert different pharmacological effects on psychological stress. Therefore, we examined the differential effects of conditioned stress on basal dopamine release and response among control (saline; SAL), antipsychotic drug (haloperidol; HAL), and mood-stabilizer (valproic acid; VPA) groups.Male Sprague Dawley rats received 2 mg/kg/day of MAP for 10 days to sensitize them to the drug, and a fear conditioning paradigm was conducted to model psychological stress. Dopamine changes in response to conditioned fear stress in the amygdala were measured by microdialysis and high-performance liquid chromatography.Compared with SAL, both the HAL and VPA groups showed inhibition of excessive dopamine release in the amygdala. HAL elevated the number of dopamine vesicles in MAP rats, but VPA did not. These results suggest that VPA-mediated alteration in the number of dopamine-containing vesicles is one of the reasons why VPA is effective in ameliorating schizophrenia symptoms.
P3-2-184 海馬のテロメア長に与える抗精神病薬の効果 Effect of antipsychotics on telomere length in the hippocampus ○鳥海和也1, 宮下光弘1, 野原泉1, 市川智恵1, 新井麻友美1, 小幡菜々子1, 糸川昌成1 ○Kazuya Toriumi1, Mitsuhiro Miyashita1, Izumi Nohara1, Tomoe Ichikawa1, Mayumi Arai1, Nanako Obata1, Masanari Itokawa1 都医学研・精神行動医学・統合失調症・うつ病1 Proj Schizophr Affect Disord Res, Dept Psychiatry Behavior Sci, Tokyo Metropolitan Inst of Med Sci, Tokyo1 Recently, leukocyte telomeres in schizophrenia patients have been reported to be shorter than that in healthy subjects. Telomere is composed of tandem TTAGGG repeats at the ends of each chromosome approximately 15 kilobases in length. Several lines of evidence suggested that telomere shortening was induced by biophysical and psychological stress, especially during neurodevelopmental period that is thought to be causative for schizophrenia. Additionally, chronic stress exposure to mice suppressed neurogenesis in the hippocampus accompanied with decrease of telomerase expression, leading to depression-like and negative symptom-like behaviors. The behavioral deficits were also induced by treatment of telomerase inhibitor in hippocampus. Although these findings suggest the association between telomere and schizophrenia, the molecular mechanism remains unclear. In this study, we first investigated the lengths of leukocyte telomeres using Japanese schizophrenia patients and discovered that the telomeres were indeed shortened as previous reports in American and European subjects with schizophrenia. Next, to evaluate the effect of antipsychotics on telomere length, we had treated mice with several types of antipsychotics for 2 weeks and found that treatment of atypical antipsychotics, such as risperidone, olanzapine and aripiprazole, but not typical antipsychotics, haloperidol, elongated the telomere length in the hippocampus. Moreover, we demonstrated that the effect of atypical antipsychotics on telomere length might be regulated by serotonin system. These findings suggest the possibility that effectiveness of atypical antipsychotics in treating negative symptom might be attributed, at least partially, to telomere length modulation.	P3-2-185 歯状回ニューロンの成熟異常を示すマウスの海馬におけるBDNF-MAPK シグナル経路の調節異常 Dysregulation of BDNF-MAPK signaling pathway in the hippocampus of mice with “immature dentate gyrus” ○小清水久嗣1, 大平耕司1,2, 萩原英雄1,2, 高雄啓三2,3, 高木豪4,5, 片岡正和6, 石井俊輔4, 高橋正身7, 宮川剛1,2,3 ○Hisatsugu Koshimizu1, Koji Ohira1,2, Hideo Hagihara1,2, Keizo Takao2,3, Tsuyoshi Takagi4,5, Masakazu Kataoka6, Shunsuke Ishii4, Masami Takahashi7, Tsuyoshi Miyakawa1,2,3 藤田保健衛生大学・総合医科学研究所・システム医科学研究部門1, 科学技術振興機構・CREST2, 生理学研究所・行動・代謝分子解析センター3, 理化学研究所・分子遺伝学研究室4, コロニー発達障害研究所・周生期学部5, 信州大学工学部・環境機能工学科6, 北里大学医学部・生化学単位7 Div. of Sys. Med. Sci., ICMS, Fujita Hlth. Univ., Aichi1, JST, CREST, Saitama2, Ctr. for Gene. Anal. of Behav., NIPS, Aichi3, Lab. of Mol. Genet., RIKEN, Ibaragi4, Instit. for Dev. Res., Aichi Pref. Colony, Aichi5, Dept. of Envr. Sci. and Tech., Fac. of Eng., Shinshu Univ., Nagano6, Dept. of Biochem., Kitasato Univ. Sch. of Med., Kanagawa7 We previously identified "immature dentate gyrus (iDG)", in which almost all the granule cells in dentate gyrus (DG) exhibit pseudo-immature status, in several gene-targeted mouse lines that display behavioral abnormalities related to psychiatric disorders, and in mice that were chronically administered with antidepressant fluoxetine (FLX) and muscarinic agonist pilocarpine. In the hippocampus of αCaMKII heterozygous knockout (HKO) mice, which exhibit iDG, we reported that expression of genes involved in brain-derived neurotrophic factor (BDNF)-MAPK pathway was dysregulated. In the present study, we further evaluated expression of the molecules related to BDNF-MAPK pathway in the hippocampus of mice with iDG, αCaMKII HKO, Shn-2 KO, SNAP-25 (Ser187Ala) knock-in (SNAP-25 KI), and FLX-administered mice. In the mice with iDG, increase of the amount of BDNF in the DG was commonly observed. Expressions of TrkB, a receptor for BDNF, were up-regulated in the hilus of the three strains of mutants, but not in that of FLX-administered mice. SNAP-25 KI mice showed ectopic expression of TrkB in the DG molecular layer. There was up-regulation of Carboxypeptidase E (CPE), an intracellular binding partner of BDNF, in Schaffer collaterals of the mice with iDG. We conducted bioinformatic analysis on the genes whose expression levels were changed in the DG or hippocampus of the mice showing iDG, and demonstrated that MAPK signaling pathway has the highest enrichment score. Although preliminary, antibody array revealed that phosphorylation of CREB, JNK, and p38 are up-regulated in the DG of αCaMKII HKO mice. These findings indicate that BDNF-MAPK pathway is commonly dysregulated in the hippocampus of the mice showing iDG. BDNF-MAPK pathway may play a major role in maturation abnormality of DG granule cells.
P3-2-186 上皮成長因子によって確立された統合失調症動物モデルにおける腹側被蓋野ー前頭皮質ドパミン経路の機能異常 Functional deficits of the ventral tegmental area - prefrontal cortex dopamine pathway of the schizophrenia animal model established by epidermal growth factor ○外山英和1, 難波寿明1, 那波宏之1 ○Hidekazu Sotoyama1, Hisaaki Namba1, Hiroyuki Nawa1 新潟大学 脳研究所 分子神経生物学1 Dept Mol Neurobiol, Niigata Univ1 Epidermal growth factor (EGF) is one of ErbB ligands and possesses a neurotrophic activity on dopaminergic neurons. Our previous study reveals that the development of central dopaminergic systems is vulnerable to peripherally circulating EGF. Neonatal exposure to EGF develops hyperdopaminergic innervation of globus pallidus, leading to a deficit in sensorimotor gating. However, the pallidal hyperdopaminergic state cannot illustrate their cognitive deficits in social interaction. To explore a potential link of the social deficits with any dopaminergic dysfunction, we assessed neural activity of the ventral tegmental area (VTA)-medial prefrontal cortex (mPFC) dopamine pathway using microdialysis and in vivo single unit recording techniques. A basal concentration of dopamine was elevated in mPFC of EGF-treated rats, whereas social stimulus-induced dopamine efflux was reduced. In agreement, we found that a mean firing rate and burst index of VTA dopamine neurons were higher in EGF-treated rats. Subchronic treatment of an antipsychotic drug, risperidone, ameliorated the abnormalities in both basal dopamine levels and social behaviors. Currently, we are investigating the chronic effect of risperidone on social stimulus-induced dopamine efflux in mPFC as well as on a unit activity of VTA dopamine neurons. Pathophysiological roles of the VTA dopamine system in social behaviors will be discussed.	P3-2-187 Forehead NIRS signal cahnges during Sternberg's task in schizophrenia ○Masao Iwase1, Michiyo Azechi2, Koji Ikezawa1, Ryouhei Ishii1, Hidetoshi Takahashi3, Takayuki Nakahachi3, Leonides Canuet4, Yasunori Aoki1, Shunichiro Ikeda1, Masahiro Hata1, Hiroaki Kazui1, Motoyuki Fukumoto1,51,5, Kazutaka Ohi1,5,6, Hidenaga Yamamori1,5,7, Michiko Fujimoto1, Yuka Yasuda1,5,8, Ryota Hashimoto1,5,8, Masatoshi Takeda1 Department of Psychiatry, Osaka University Graduate School of Medicine1, Department of Psychiatry, National Hospital Organization, Osaka National Hospital2, Department of Child and Adolescent Mental Health, National Center of Neurology and Psychiatry3, Euroespes Biomedical Research Center, Spain4, CREST, JST5, National Hospital Organization, Yamato Mental Medical Center6, Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine7, The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Osaka University Graduate School of Meicine, Japan8 To assess the utility of forehead NIRS signal changes as biomarkers to discriminate schizophrenia from healthy controls. We enrolled 144 patients with schizophrenia and 271 healthy controls. Forehead NIRS signal changes (oxyhemoglobin, deoxyhemoglobin, tissue oxygen index) were measured during a working memory test (Stenberg's task). ROC curve analysis were performed. Patients with schizophrenia showed significantly reduced changes of NIRS signals duiring Sternberg's task. However, ROC curve analysis indicated relatively low AUC values in this task. Though forehead NIRS signals indicated significant difference between schizophrenia and healthy subjects, the utility of NIRS signals as biomarkers was considered quite limited.
P3-2-188 PAPST1遺伝子と統合失調症との関連研究 Genetic association study of PAPST1 ( 3'-Phsophoadenosine 5'-Phosphosulfate Transporter 1 ) with schizophrenia ○治徳大介1, 山本直樹1, 岩山佳美2, 吉川武男2, 上里彰仁1, 車地暁生1, 西川徹1 ○Daisuke Jitoku1, Naoki Yamamoto1, Yoshimi Iwayama2, Takeo Yoshikawa2, Akihito Uezato1, Akeo Kurumaji1, Toru Nishikawa1 東京医科歯科大学大学院 医歯学総合研究科 精神行動医科学分野1, 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2 Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, Tokyo, Japan1, Lab. for Molecular Psychiatry, RIKEN BRAIN SCIENCE INSTITUTE, Wako, Japan2 Many studies have suggested that the N-methyl-D-aspartate (NMDA) type glutamate receptor dysfunction may be causally involved in the pathogenesis of schizophrenia. D-serine in mammalian brains has been suggested to be an endogenous co-agonist of the NMDA-type glutamate receptor. We previously indentified 3'-phosphoadenosine 5'-phosphosulfate transporter 1 (PAPST1) as a molecule that facilitates the release of D-serine from cells. Therefore, we hypothesized altered function of PAPST1 might be associated with the pathophysiology of schizophrenia. In the present study, we examined 8 tag SNPs (SNP01 - SNP08) located within the 10 kb up- and down-stream regions of PAPST1 gene for genetic association with schizophrenia in a case-control study of Japanese cohort with 2012 cases and 2170 control subjects. The current study was approved by the Ethics Committees of Tokyo Medical and Dental University and RIKEN. All participants gave written informed consent to participate in the study. Allelic tests showed nominally significant association of SNP02 with schizophrenia (P = 0.035, odds ratio [OR] = 1.098). Genotypic tests showed significant association of the SNP02 (P = 0.005). In haplotype analysis, haplotypes including SNP02 showed nominal significance (P = 0.028 and 0.030). Of these associations, genotypic significant association remained even after correction for multiple testing (P = 0.030). SNP02 is located at about 3kb upstream from PAPST1. Therefore, this SNP may be associated with the transcriptional regulation of PAPST1 and/or the adjacent genes. The present study suggests that PAPST1 may confer the genetic risk for schizophrenia.	P3-2-189 CNS特異的なDISC1結合タンパク質DBZはオリゴデンドロサイトの分化を促進する DBZ, a CNS-specific DISC1 binding protein, positively regulates oligodendrocyte differentiation ○清水尚子1, 小山佳久2, 服部剛志3, 宮田信吾1, 片山泰一4, 伊藤彰3, 遠山正彌1 ○Shoko Shimizu1, Yoshihisa Koyama2, Tsuyoshi Hattori3, Shingo Miyata1, Taiichi Katayama4, Akira Ito3, Masaya Tohyama1 近畿大・東洋医学研究所・分子脳科学研究部門1, 大阪大院・医・神経機能形態学2, 大阪大院・医・分子精神神経3, 大阪大院・大阪大、金沢大、浜松医科大連合小児発達学研究科・こころの発達神経科学4 Div. of Mol. Brain Sci., Res. Inst. of Traditional Asian Med., Kinki Univ., Osaka1, Dept. of Anat. and Neurosci., Grad. Sch. of Med., Osaka Univ., Osaka2, Dept. of Mol. Neuropsychiatry, Grad. Sch. of Med., Osaka Univ., Osaka3, Dept. of Child Development and Mol. Brain Sci., United Grad. Sch of Child Development, Osaka Univ., Kanazawa Univ. and Hamamatsu Univ. Sch. of Med., Osaka4 Schizophrenia (SZ) is a serious and disabling mental disorder with a lifetime prevalence of about 1% of the population worldwide, and commonly has a chronic course. The underlying pathological mechanisms are still largely unknown, but a growing body of evidence suggests that it is a multifactorial disorder influenced by genetic, neurodevelopmental and social factors. Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1;11) (q42.1;q14.3) translocation that segregates with major psychiatric disorders including schizophrenia, recurrent major depression and bipolar affective disorder in a Scottish family. Here we report that DBZ (DISC1 Binding Zinc-finger protein), a brain-specific member of DISC1 interactome, positively regulates oligodendrocyte differentiation. In an in vitro oligodendrocyte primary culture, the expression of DBZ was increased after induction of differentiation of oligodendrocyte by deprivation of PDGF and siRNA knockdown of DBZ decreased the expression level of myelin related markers such as MBP, MAG and CNPase. In mouse corpus callosum, DBZ mRNA expression in oligodendrocyte was intense at P7, the period of myelination, and it was hardly detectable in adult by in situ hybridization. Furthermore, a delay of oligodendrocyte maturation in DBZ knockout mice was revealed by the electron microscope analysis. These results indicate that DBZ is involved in oligodendrocyte differentiation. As multiple lines of evidence obtained by brain imaging, studies in postmortem brains and genetic association studies have implicated oligodendrocytes and myelin dysfunction in SZ, these results may provide important clue about the underlying etiology of SZ.
P3-2-190 統合失調症患者死後脳におけるLINE-1コピー数の増大 Increased copy number of LINE-1 in the brains of patients with schizophrenia ○文東美紀1, 宮内妙子2, 上田順子2, 小森敦子2, 笠井清登3, 加藤忠史2, 岩本和也1 ○Miki Bundo1, Taeko Miyauchi2, Junko Ueda2, Atsuko Komori2, Kiyoto Kasai3, Tadafumi Kato2, Kazuya Iwamoto1 東京大院・医・分子精神1, 理研・BSI・精神疾患動態2, 東京大院・医・精神医学3 Dept. of Molecular Psychiatry, Grad. Sch. Med., Univ. Tokyo, Tokyo, Japan1, Lab. for Molecular Dynamics of Mental Disorders, RIKEN BSI, Wako, Japan2, Dept. of Neuropsychiatry, Grad. Sch. Med., Univ. Tokyo, Tokyo, Japan.3 LINE-1 (long interspersed nuclear element -1) is one of non-LTR retrotransposons, which encode the proteins with reverse transcriptase and endonuclease activities, and can retrotranspose itself. The human genome contains about 500,000 copies of LINE-1. Most of them lost the retrotransposition activity, because of incomplete reverse-transcription or accumulation of mutations. However, about 50 copies still can retrotranspose their copies in the germ line cells. Recently, it has been reported that the LINE-1 also had retrotransposition activity in the neural progenitor cells. Consequently, copy number of LINE-1 in brain was increased compared with other tissues in the same individual. As the retrotransposition may occur near or within the genes, increased retrotransposition activity or ectopic insertions could be related to the pathophysiology of psychiatric disorders such as schizophrenia. We quantified copy number of LINE-1 in two independent postmortem prefrontal cortex sample sets. Samples consist of schizophrenia, bipolar disorder, major depression and controls. Both sample sets were obtained from the Stanley Medical Research Institute. Copy number of the LINE-1 was determined by real time PCR method, according to the previous report (Coufal et al, Nature 2009). We calculated the relative LINE-1 content of brain/liver in the first set. In the second set, we separated brain tissue into neuronal and non-neuronal cell nuclei using the NeuN-based sorting technique, and calculated relative LINE-1 content of neuron/non-neuron. There were significant increases in relative LINE-1 contents in schizophrenia in both sample sets. Confounding factors such as age, gender, postmortem interval, and sample pH did not affect the LINE-1 content in the brains. These results suggest that aberrant retrotransposition activity in the neural progenitor cells may be associated with the pathophysiology of schizophrenia.	P3-2-191 2種の幼若期栄養因子投与マウスのin vivo麻酔下での中脳ドパミン神経活動変化 Abnormal firing activities of the midbrain dopaminergic neurons in the mice treated with EGF and neuregulin-1 as neonate ○難波寿明1, 大久保猛司1, 那波宏之1 ○Hisaaki Namba1, Takeshi Okubo1, Hiroyuki Nawa1 新潟大学脳研究所分子神経生物学1 Dept of Mol Neurobiol, Brain Res Inst, Niigata Univ, Niigata1 Epidermal growth factor (EGF) and neuregulin 1 (NRG1) are implicated in dopamine-associated brain diseases, such as schizophrenia. These factors both exert a neurotrophic activity on midbrain dopaminergic neurons, binding to ErbB1 and ErbB4 receptors expressed in this neuronal population. In agreement, neonatal administration of EGF and neuregulin-1 enhances the development of dopaminergic terminals in the striatum and/or medial frontal cortex and induce schizophrenia-like behavioral abnormality. We previously found that the channel property and/or synaptic inputs of midbrain dopaminergic neurons are altered following EGF treatment. To test whether these alterations in slice preparations result in those in firing activity in vivo, single unit extracellular recordings were performed in chloral hydrate-anesthetized mice. In EGF-treated mice, there was an increase in bursting rates, whereas these were no significant differences in the mean firing frequency or bursting rates in NRG1-treated mice. Thus, neonatal EGF challenge has more prominent effects on the firing activity of dopaminergic neurons than NRG1. The observed differences in EGF and NRG1 effects on dopamine neurons might illustrate the behavioral variation between the mice treated with these factors.
P3-2-192 統合失調症モデルマウスの前頭前野におけるパルバルブミン陽性細胞の減少とペリニューロナルネット発現の変化 Decreased parvalbumin immunoreactivity and altered perineuronal net labeling in the frontal cortex of schizophrenia model mice ○萩原英雄1,2, 高木豪3,4, 石井俊輔3宮川剛1,2,6 ○Hideo Hagihara1,2, Tsuyoshi Takagi3,4, Shunsuke Ishii3, Isabella A Graef5, Gerald R Crabtree5, Tsuyoshi Miyakawa1,2,6 藤田保健衛生大・総医研・システム医科学1, 理化学研究所・筑波研究所・分子遺伝学研究室3, 愛知県心身障害者コロニー・発達障害研究所4, スタンフォード大学5, 自然科学研究機構・生理研・行動代謝分子解析センター6 Div of Sys Med Sci, ICMS, Fujita Hlth Univ, Aichi1, CREST, JST, Saitama2, Lab of Mol Genet, RIKEN, Ibaragi3, Instit for Dev Res, Aichi Pref Colony, Aichi4, Dept of Pathol, Stanford Univ Sch Med, Stanford, CA5, Ctr for Gene Anal of Behav, NIPS, Aichi6 Alterations in GABAergic interneurons in prefrontal cortex, including decreased levels of parvalbumin (PV), are well replicated in schizophrenia and may underlie some of the cognitive deficits seen in the disorder. Recently, it was shown that PV is gradually expressed during maturation in fast-spiking interneurons and could be used as a maturation marker of this type of interneurons (Gandal et al, 2012). These neurons are increasingly enwrapped by perineuronal nets (PNNs) with progression of postnatal development. PNNs are involved in neuronal maturation or synapse stabilization, and in the closure of critical period in visual cortex. PNNs abnormalities are proposed to contribute to several aspects of the pathophysiology of schizophrenia (Pantazopoulos et al, 2010). To date, we have shown that forebrain-specific calcineurin knockout (CN KO) mice, αCaMKII heterozygous KO (HKO) mice and Schnurri-2 (Shn-2) KO mice show schizophrenia-relevant behaviors concomitant with maturation abnormalities of granule cells in their dentate gyrus (DG). However, it is not known whether PV-positive and PNNs-positive neurons are affected in these model mice. In this study, using immunohistological analysis, we evaluated expression of PV and PNNs in the medial frontal cortex (mFC) of these mice. In three strains of mutants, the number of PV-positive cells was decreased in the mFC. In Shn-2 KO mice, we found a decrease in the percentage of PNNs and PV double-positive cells per total PV-positive cells. On the other hand, in CN KO mice and αCaMKII HKO mice, there were no significant differences in the percentage in comparison to control littermates. These results suggest that PV neurons of these mice have a maturation failure or a reversal of maturation status (de-maturation), and that immaturity of neurons can be seen not only in the DG but also in the other brain regions. The immaturity of PV neurons as well as dentate granule cells may be potential therapeutic targets of schizophrenia.	P3-2-193 Withdrawn
P3-2-194 Ccd1/Dixdc1欠損マウスにおける行動異常 Behavioral abnormalities in the mice lacking Coiled-coil-DIX 1 (Ccd1)/ DIX domain containing 1 (Dixdc1) gene ○桝正幸1, 昌子浩孝2, 塩見健輔1, 宮川剛2, 桝和子1 ○Masayuki Masu1, Hirotaka Shoji2, Kensuke Shiomi1, Tsuyoshi Miyakawa2, Kazuko Keino-Masu1 筑波大学　医学医療系　分子神経生物学1, 藤田保健衛生大学　総合医科学研究所システム医科学研究部2 Dept Mol Neurobiol, Unv of Tsukuba, Tsukuba1, Inst Compr Med Sci, Fujita Health Univ2 Wnt signaling plays important roles in cell proliferation, differentiation, migration, and morphogenesis. Wnt activates distinct pathways, including canonical β-catenin pathway, planar cell polarity pathway, and Ca2+ pathway. Intracellular signaling of the canonical pathway is mediated by two antagonistic molecules dishevelled and axin. When Wnt signal is absent, axin promotes β-catenin phosphorylation and degradation by stabilizing APC complex, whereas when Wnt is present, disheveled inhibits APC complex, leading to accumulation of phosphorylated β-catenin in the nucleus. Dishevelled and axin have a conserved DIX domain and form homomeric and heteromeric complexes through the domain, which is essential for the canonical β-catenin pathway. We isolated a third DIX-domain containing molecule, Coiled-coil-DIX 1 (Ccd1) in zebrafish embryos. Ccd1, also called DIX domain containing 1 (Dixdc1), forms homomeric and heteromeric complexes with disheveled and axin, and activates Wnt/β-catenin pathway. In mice, Ccd1 is expressed in the nervous system from early stages of development, and Ccd1 expression persists in almost all the neurons in the adult brain. Recently, Ccd1 was identified as one of the proteins that bind to DISC1 (Disrupted in schizophrenia 1). DISC1 is a protein encoded by a gene that is disrupted by chromosomal translocation in a Scottish family genetically predisposed to schizophrenia, bipolar disorder and other psychiatric disorders. Ccd1 binds to DISC1 to activate Wnt signaling, and regulate proliferation of neural progenitors and neuronal migration in the cerebral cortex. To examine the possible roles of Ccd1 gene in psychotic disorders, we performed systematic analysis of behavioral abnormalities using Ccd1 knockout mice that were generated by Laboratory for Animal Resources and Genetic Engineering at RIKEN Center for Developmental Biology. We found abnormalities in the tests related to anxiety.	P3-2-195 ニューレグリン前駆体の細胞内輸送機構 Molecular regulation of pro-Neuregulin intracellular trafficking ○森大輔1, 貝淵弘三1 ○Daisuke Mori1, Kozo Kaibuchi1 名古屋大院・医・神経情報薬理1 Dept Cell Pharmacology, Nagoya University, Nagoya, Japan1 The schizophrenias have a lifetime prevalence of approximately 1% in the general population and give a serious and intractable mental disorder. It has not been still cleared the molecular mechanism of the schizophrenia onset to date. Recently, the assumption of the onset has been potentially confident of the developmental disability on central nervous system. Furthermore, schizophrenia is known to be multifactorial disease participating in not only a genetic factor but also an environmental factor during embryonic stage, perinatal stage, or adolescence. Many genomic analyses of schizophrenia patients have reported the candidate genes for onset risk of the symptom, resulting DISC1 is the most possible factor by the evidence of Scottish-descent analysis. We have focused on the signal network among the onset risk genes of DISC1 and DISC1 interacting proteins and analyzed globally the molecular interaction of signal transduction proteins to be constituted with the network in various types of neurons, in purpose of the clarification of the pathogenic mechanism of schizophrenia.To elucidate the pathogenic mechanism of schizophrenia, we have analyzed DISC1 localization and function in neuronal cells. Our anti-DISC1 antibody enabled us to observe clear localization to Golgi apparatus in cultured neuron prepared from developing hippocampus. We hypothesized that DISC1 would be involved in vesicular transport of various proteins and mRNAs which maintain neuronal function. Previously, we have identified direct interaction of DISC1 and Neuregulin-1, which is a ligand of ErbB3 and ErbB4. To understand the sense of their association, we have attempted to develop a new experimental system that enables us to analyze the vesicles included with transmembrane proteins from Trans-Golgi network in a synclonized manner. In this presentation, our result using this system suggested that DISC1 was involved in regulating pro-Neuregulin-1 transport.
P3-2-196 海馬神経細胞においてDISC1はIP3受容体mRNAの輸送を制御する DISC1 regulates transport of IP3R1 mRNA in hippocampal neurons ○坪井大輔1, 黒田啓介1, 飯塚幸彦1, 貝淵弘三1 ○Daisuke Tsuboi1, Keisuke Kuroda1, Yukihiko Iizuka1, Kozo Kaibuchi1 名古屋大学大学院 医学系研究科 神経情報薬理学1 Dept Cell Pharmacology, Univ of Nagoya, Nagoya1 Disrupted-In-Schizophrenia 1 (DISC1) is a susceptibility gene for major psychiatric disorders. DISC1 is implicated in a variety of processes during neuronal development like neurogenesis, neuronal migration, axon formation, dendritic arborization and synapse formation. However, its mode of action remains largely unknown. Here, we comprehensively screened the DISC1-interacting proteins by proteomic analysis and identified many RNA-binding proteins including Hzf, which acts as a component of RNA-transport granules and participates in the dendritic transport of IP3 receptor type 1 (IP3R1) DISC1 directly interacted with Hzf and co-localized with Hzf and RNA granules in hippocampal dendrites. DISC1 directly associated with IP3R1 mRNA and was co-transported into dendrites. Impairment of DISC1 function prohibited dendritic transport and BDNF-induced translation of IP3R1 mRNA. These results suggest that DISC1 together with Hzf interact with specific mRNAs such as IP3R1 mRNA and regulate their dendritic transport as a component of RNA granules.	P3-2-197 統合失調症、気分障害の脳脊髄液中モノアミン代謝産物の解析 Analyses of monoamine metabolites in the cerebrospinal fluid of patients with schizophrenia and mood disorders ○服部功太郎1,2, 篠山大明1, 寺石俊也1, 藤井崇1, 吉田寿美子3, 有馬邦正3, 功刀浩1 ○Kotaro Hattori1,2, Daimei Sasayama1, Toshiya Teraishi1, Takashi Fujii1, Sumiko Yoshida3, Kunimasa Arima3, Hiroshi Kunugi1 国立精神・神経医療研究センター　神経研究所　疾病研究第3部1, 国立精神・神経医療研究センター　トランスレーショナル・メディカル・センター2, 国立精神・神経医療研究センター病院3 Dept Mental Disorder Res, Nat Inst Neurosci, Nat Center Neurology and Psychiatry, Tokyo1, Translational Medical Center, Nat Center Neurology and Psychiatry, Tokyo2, Nat Center Neurology and Psychiatry Hospital, Tokyo3 Monoamine neurotransmitters such as dopamine and serotonin play crucial roles in psychiatric disorders including schizophrenia. The levels of monoamine metabolites, i.e., homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindole acetic acid (5-HIAA) in the cerebrospinal fluid (CSF), reflect the releases of dopamine, noradrenalin and serotonin respectively in the brain. Thus, in the present study, we aimed to examine the possible use of CSF monoamine metabolites as biomarkers for mental disorders including schizophrenia and mood disorders. Subjects were 56 patients with schizophrenia, 52 major depression, 20 bipolar disorder and 50 healthy controls. After psychiatric and neurologic examinations, a lumbar puncture was done in a standardized manner and CSF was analyzed by HPLC for each metabolite. We found that CSF HVA levels were significantly increased in the schizophrenia group compared to the control group. Among the schizophrenia subjects, HVA levels were negatively and significantly correlated with the severities of symptoms. We also found CSF levels of 5-HIAA or MHPG were significantly decreased in patients with major depression, compared to the controls. The 5-HIAA or MHPG levels tended to be decreased in bipolar disorder. Our results suggest that the measurement of CSF metabolites could be used as biomarkers for psychiatric disorders.
P3-2-198 The emerging role of AKT1 in the modulation of parvalbumin-containing GABAergic interneurons and GABA type A receptors both in vitro and in vivo: implication for the pathogenesis of schizophrenia ○Chia-Yuan Chang1, Yi-Wen Chen1, Tsu-Wei Wang2, Wen-Sung Lai1 National Taiwan Uniuversity1, Department of Life Science, National Taiwan Normal University, Taipei, Taiwan2 Accumulating evidence suggests that multiple susceptibility genes might contribute to the pathogenesis of schizophrenia, including AKT1 and GABA type A (GABA(A)) receptor subunit genes. Reduction of the parvalbumin-containing subpopulation of GABAergic neurons and GABA(A) receptor &beta2 subunits was reported in the dorsolateral prefrontal cortex of schizophrenic patients. Activation of AKT promoted differentiation of neural progenitor cells into GABAergic neurons and increased the number of GABA(A) receptors on the plasma membrane surface in cell culture. But the possible interaction between AKT1 and GABA remains much unclear. Two sets of experiments were conducted in this study. In the 1st set, an in vitro model using P19 embryonal carcinoma cells was applied to investigate the effect of AKT1/2 inhibitor on the expression of GABAergic neuron. Our results revealed that AKT1/2 inhibitor resulted in a 40% reduction of GAD67-positive neurons and a 60% reduction of parvalbumin-positive neurons, respectively. No significant difference was found in the expression of GABA(A) receptors on the plasma membrane. In the 2nd set, Akt1 knockout mice were used to reveal the effect of AKT1 on GABA synapses in vivo. Taking advantage of pentylenetetrazol (PTZ, a GABA(A) receptor antagonist), female Akt1 knockout mice exhibited less severe PTZ-induced convulsive activity compared with their wild-type controls, suggesting that Akt1 deficiency might dampen the disinhibition of PTZ through GABAergic interneurons, especially in females. Quantitative analyses of immunostained GABAergic interneurons further revealed that there was a reduction of parvalbumin-positive interneurons in the hippocampus and primary motor cortex of Akt1 knockout female mice. A reduction of functional GABA(A) receptors and impairments of hippocampus-dependent cognitive functions were also found in Akt1 knockout female mice.	P3-2-199 Investigating gene-environment interactions in schizophrenia-related phenotypes using neonatal immune challenge in Akt1 mutant mice as a model ○Wan-Rong Wong1, Ching-Hsun Huang2, Wen-Sung Lai1,2 Inst Brain and Mind Sciences, National Taiwan Univ, Taipei, Taiwan.1, Dept Psychol, National Taiwan Univ, Taipei, Taiwan2 Schizophrenia appears to be a multifactorial disorder with a strong genetic predisposition. Accumulating evidence suggests ,Akt1 (protein kinase B α) may contribute to susceptibility for schizophrenia. Akt1 mutant mice also displayed neuromorphological and behavioral abnormalities. In addition to genetic predisposition, early infection-induced disruption in neurodevelopment may cause long-lasting changes, leading to functional deterioration and the onset of schizophrenia in later life. Indeed, immuno-precipitated neurodevelopmental animal models displayed aberrant behavioral functions, and perinatal infection altered the immune response as well as learning in adulthood in rats. Alteration of Akt1 expression was also observed in prenatal immune challenged mice. Given the existing evidence, the objective of this study is to examine whether early infection alone or its interaction with Akt1 deficiency may be pertinent to the vulnerability of schizophrenia-like endophenotypes and neurochemical abnormalities in adult mice. Akt1 heterozygous pups and their wild-type littermate controls received daily injections of polyriboinosinic-polyribocytidylic acid (polyI:C) from postnatal days 2 to 6 to induce antiviral response. Data acquired by cytometric bead array displayed altered cytokine expression levels in the brains of polyI:C-treated pups. Afterward, a battery of behavioral tasks and neurochemical assays were conducted in adult mice. Our preliminary data revealed impairments of spatial memory and social recognition in polyI:C-treated mice. Further behavioral and neurochemical analyses are still in progress. Findings from this study will provide some clues to the understanding of gene-environment interaction in the pathogenesis of schizophrenia-related phenotypes.
P3-2-200 A sex- and region-specific role of Akt1 in the modulation of methamphetamine-induced hyperlocomotion and striatal neuronal activity: implications in schizophrenia and methamphetamine-induced psychosis ○Wen-Sung Lai1, Yi-Wen Chen1, Hui-Yun Kao2, Ming-Yuan Min2 Department of Psychology, National Taiwan University1, Institute of Zoology, National Taiwan University2 AKT1 (protein kinase B, alpha) is involved in multiple biological processes and several severe psychiatric disorders, including schizophrenia and methamphetamine (Meth) use disorder. AKT is downstream to dopamine D2 receptors and AKT signaling cascade might be involved in the expression of dopamine-dependent behaviors. Meth-associated psychosis has been considered a pharmacological or environmental disease producing agent model of schizophrenia. Given the involvement of AKT1 in the dopamine signaling cascade and in the pathogenesis of Meth abuse disorder and schizophrenia, the aim of this study is to investigate the sex-specific role of AKT1 in the regulation of Meth-induced behavioral sensitization and the alterations of striatal neurons using Akt1-/- mice and wild-type controls. A serial of experiments was conducted and Meth was used to induced hyperlocomotion and behavioral sensitization. Our findings indicate that (1) male Akt1-/- mice were less sensitive to Meth-induced hyperlocomotion during Meth challenge, whereas female Akt1-/- mice did not exhibit such reduction; (2) sex differences were also revealed by co-injections of Meth with raclopride (but not SCH23390) in the suppression of hyperlocomotion in Meth-sensitized Akt1-/- males but not females; (3) Meth-induced alterations of brain activity were revealed in the striatum of male Akt1-/- mice using microPET with 18F-FDG, whereas Akt1-/- males did not exhibit genotypic alterations of neurotransmitters in the brain; (4) the deficiency of Akt1 has significant impact on the alterations of electrophysiological and neuromorphological properties of striatal MSNs; and (5) subchronical injections of 17beta-estradiol recaptured the reduction of Meth-induced hyperactivity in Meth-sensitized Akt1-/- males. This study highlights a sexual- and region-specific effect of Akt1 in dopamine-dependent behaviors and implies the importance of AKT1 in the modulation of sex differences in Meth use disorder and schizophrenia.	P3-2-201 A sex- and hippocampal- specific role of neuregulin 1 in the regulation of hippocampus-dependent cognitive function and GABAergic interneurons in neuregulin 1 mutant mice ○Ju-Chun Pei1, Chen Ching1, Yi-Wen Chen1, Wen-Sung Lai1,2,3 Department of Psychology, National Taiwan University, Taiwan1, Neurobiology and Cognitive Science Center, National Taiwan University, Taiwan2 Accumulating evidence from human and animal studies suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 belongs to the neuregulins family of growth factors and its expression has been found in many brain regions, especially in the hippocampus. Emerging studies start to reveal that NRG1 signaling is related to the neural plasticity which may be responsible for the cognitive deficits in schizophrenic patients. To determine the involvement of NRG1 in hippocampus-related cognitive functions and the importance of NRG1 in the regulation of hippocampal neuromorphology and GABAergic interneurons, both male and female transmembrane-domain NRG1 heterozygous mutant mice and their wild-type littermates were used in a series of experiments. First, a comprehensive battery of behavioral tasks revealed that NRG1-deficient mice (especially males) exhibited significant impairments of cognitive functions. Second, neuromorphological analysis of pyramidal neurons in the CA1 region of hippocampus was conducted in these mice and no significant morphological alteration was found. Third, pharmacological challenges (including MK-801, pentylenetetrazol (PTZ), and methamphetamine) were conducted in these mice and our data indicated that NRG1 deficiency might alter GABAergic activity in the brain. Forth, we further confirmed that a reduction of GAD67 and parvalbumin expressing level in the hippocampus of NRG1 mutant males but not in females. Fifth, the treatment of Valproate can rescue observed behavioral deficits in NRG1 mutant males. Collectively, there results indicated the importance of NRG1 in the regulation of hippocampus-related cognitive functions and the expression of hippocampal GABAergic interneurons, especially in males.

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