統合失調症
Schizophrenia
O3-7-6-1
MTHFR機能多型と統合失調症の遺伝子関連研究
Functional variants of the MTHFR gene and schizophrenia in the Japanese population

○西晃1, 沼田周助1, 田嶋敦2, 木下誠1, 下寺信次3, 大井一高4, 橋本亮太4,5, 井本逸勢2, 武田雅俊4,5, 大森哲郎1
○Akira Nishi1, Shusuke Numata1, Atsushi Tajima2, Makoto Kinoshita1, Shinji Shimodera3, Kazutaka Ohi4, Ryota Hashimoto4,5, Issei Imoto2, Masatoshi Takeda4,5, Tetsuro Ohmori1
徳島大院・ヘルスバイオサイエンス・精神医学1, 徳島大院・ヘルスバイオサイエンス・人類遺伝学2, 高知大・医・精神神経科学3, 大阪大院・医・精神医学4, 大阪大院連合小児発達学・子どものこころの分子統御機構研究センター5
Dept Psychiat, Univ of Tokushima Grad, Tokushima, Japan1, Dept Human Genetics, Univ of Tokushima Grad, Tokushima, Japan2, Dept Neuropsychiat, Univ of Kochi, Kochi, Japan3, Dept Psychiat, Univ of Osaka Grad, Osaka, Japan4, Mol Res Center for Children's Mental Develop, United Grad School of Child Develop, Univ of Osaka, Osaka, Japan5

Object: Methylenetetrahydrofolate reductase (MTHFR) is the essential enzyme in the folate-mediated single-carbon transfer reactions. Many genetic association studies between schizophrenia (SCZ) and this gene have been conducted. However, the results of these studies are controversial. We examined whether the two common functional variants in this gene, rs1801133 (C677T) and rs1801131 (A1298C) were implicated in SCZ.Methods: A case-controlled association study of these two variants with SCZ was performed (1149 SCZ and 2308 CON). Next, a meta-analysis of these two variants based on Japanese subjects was carried out (3695 SCZ and 5142 CON for rs1801133 and 1844 SCZ and 3033 CON for rs1801131). Genotyping was performed using the Taqman assay. A fixed-effects meta-analysis was performed by the R package metafor. All subjects who participated in this study were of unrelated Japanese origin and all of them signed written informed consent approved by the institutional ethics committees of the University of Tokushima Graduate School, Kochi Medical School and the University of Osaka Graduate School.Results: No significant differences were observed between two groups in allelic frequencies (rs1801133, P = 0.068; rs1801131, P = 0.273, respectively) in our cohort. However, a subsequent meta-analysis demonstrated a significant association of MTHFR 677T allele with the risk of SCZ (OR = 1.082, 95% CI = 1.089-1.151, P = 0.012). Now, we are examining the effect of this risk allele on several intermediate phenotypes.Conclusion: Our results provided support evidence for the involvement of the MTHFR gene in SCZ.
O3-7-6-2
中枢刺激薬methamphetamine応答遺伝子:発現、機能、および統合失調症における遺伝子関連解析
Psychostimulant methamphetamine-induced genes: expression, characterization and genetic association with schizophrenia

○山本直樹1, 海野真一1, 村岡新一郎1, 海野麻未1, 治徳大介1, 岩山佳美2, 吉川武男2, 西川徹1
○Naoki Yamamoto1, Masakazu Umino1, Shinichiro Muraoka1, Asami Umino1, Daisuke Jitoku1, Yoshimi Iwayama2, Takeo Yoshikawa2, Toru Nishikawa1
東京医科歯科大院・医歯・精神行動医科学1, 理化学研究所脳科学総合研究センター分子精神科学2
Dept Psychiatry and Behav Sci, Tokyo Medical and Dental Univ Grad School, Tokyo, Japan1, Lab Mol Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan2

Schizophrenic symptoms and their pharmacological behavioral models induced by psychostimulants, e.g., methamphetamine and cocaine, are usually observed after the puberty in humans or after the weaning period in rats. This development-dependent nature of the onset can be hypothesized to be associated with the maturation of the brain information processing systems that are specifically disturbed in schizophrenia or its animal models. Using a microarray technique, we have identified several developmentally regulated and methamphetamine (MAP)-induced genes from the rat cerebral neocortex as the novel candidates for the schizophrenia-related molecules. We found 20 genes whose expression levels were elevated at the postnatal day (PD) 18, 25 and 50, while 24 genes were up-regulated only after the critical period around postnatal weeks 3 for the adult-type of MAP-induced abnormal behavior that has been considered to be a model for schizophrenia (at PD 25 and 50). We have further characterized mrt3 (MAP-responsive transcript 3) gene. From unique feature of the responsiveness to MAP and cocaine as well as genetic association of human mrt3-related gene with schizophrenia, it is suggested that mrt3 gene product might play a crucial role in the formation of behavioral sensitization by these psychostimulants, as well as the development of schizophrenic symptoms.The present study was approved by ethics committees of the institutes. All participants gave informed and written consent to participate in the study.
O3-7-6-3
Independent and sex-specific effects of BDNF depletion and late adolescent methamphetamine treatment on behaviours relevant to schizophrenia in mice
○Elizabeth Manning1, Maarten van den Buuse1
The Florey Institute of Neuroscience and Mental Health1

Methamphetamine (METH) users have an increased incidence of psychosis and schizophrenia. Therefore animal models of METH use may provide insight into the pathophysiology of psychosis in METH users, and schizophrenia more broadly. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of schizophrenia, and also plays a role in the neuronal response to stimulant drugs such as METH. We are interested in whether BDNF may be involved in the development of schizophrenia in METH users.To address this question, BDNF heterozygous mice (HETs) were treated with METH from 6-9 weeks of age, a period during mouse development that corresponds to late adolescence, a critical period for schizophrenia onset in humans. Following a 2 week break, mice were tested in adulthood in paradigms relevant to the positive and cognitive symptoms of schizophrenia. BDNF HETs showed reduced prepulse inhibition (PPI) at baseline, which is a measure of sensorimotor gating. Male BDNF HETs also showed an increased sensitivity to the PPI-disrupting effects of an amphetamine (AMPH) challenge irrespective of METH pre-treatment, whereas METH-treated females showed a reduced sensitivity to AMPH challenge irrespective of genotype. In contrast, short term spatial memory in the Y-maze was unaffected by genotype and METH treatment.BDNF does not appear to play a role in the development of behaviours that are relevant to schizophrenia in mice treated with METH. METH treatment on its own resulted in tolerance to the effects of AMPH challenge to disrupt PPI in female mice. In contrast, BDNF depletion in male mice caused an increased sensitivity to the effects of AMPH on PPI. Memory in the Y-maze was unaffected by METH treatment, however investigation in complex cognitive tasks is warranted to further characterize this aspect of their phenotype. These findings show that BDNF and METH have sex-specific and independent effects on behaviours related to the positive symptoms of schizophrenia.
O3-7-6-4
Functional connectivity of the dentate gyrus is altered in schizophrenia
○New Fei Ho1,3, Juan Eugenio Iglesias2,3, Daphne Holt1,3, Joshua Roffman1,3
Department of Psychiatry, Massachusetts General Hospital1, Department of Radiology, Massachusetts General Hospital2, Havard Medical School3

Neuroimaging studies have consistently shown hippocampal abnormalities in schizophrenia, but it is not known whether all subregions of the hippocampus are equally affected. To address this question, we first determined whether distinct functional connectivity networks can be reliably identified for subregions CA1, CA2-3 and dentate gyrus (DG), and then examined the subregion-specific functional networks in schizophrenia. High-resolution structural T1- and T2-, and T2*-blood oxygenation level dependent (BOLD) scans (acquired at rest) from two independent datasets of 85 healthy subjects each and 43 patients with chronic schizophrenia were collected using 3-T Siemens magnetic resonance imaging scanners. Probabilistic subregion maps were defined on individual subject structural images and mapped onto their BOLD images. Spontaneous, low-frequency BOLD activity was extracted and correlations of subregion voxels' activity over time with the activity of other voxels over time across the whole brain were identified. Topographically distinct, robust and reproducible subregion functional networks were identified on both healthy subject cohorts. While all subregions exhibited strong connectivity locally and to the precuenus and ventromedial prefrontal cortex, dissociable large-scale networks were also observed e.g. stronger coupling of DG with superiorfrontal and posterior cingulate cortices. In patients with schizophrenia, greater left DG – local and temporal cortex coupling and less DG – superiorfrontal and anterior cingulate cortex coupling compared to controls were observed; no between-group differences in CA1 and CA2-3 functional networks were found. Lastly, the volumes of left (but not right) subregions were significantly smaller in patients. Our findings reveal differential hippocampal subregion networks in healthy humans, and also suggest alteration of left DG functional network in schizophrenia that may relate to structural changes.
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