その他の精神障害 Other Psychiatric Disorders
P2-2-231 セロトニンおよびドパミントランスポーターを過剰発現させたPC12およびHEK293細胞において、PCLOのSNPはモノアミン取り込みを制御する PCLO SNP regulates DA and 5-HT uptake in their transporter over expressed PC12 or HEK293 cells ○宇野恭介1, 高山佳奈子1, 徐承姫1, 大井一高2, 橋本亮太2,3, 西澤大輔4, 池田和隆4, 酒井規雄5, 鍋島俊隆6, 宮本嘉明1, 新田淳美1 ○Kyosuke Uno1, Kanako Takayama1, Seunghee Seo1, Kazutaka Ohi2, Ryota Hashimoto2,3, Daisuke Nishizawa4, Kazutaka Ikeda4, Norio Sakai5, Toshitaka Nabeshima6, Yoshiaki Miyamoto1, Atsumi Nitta1 富山大学大学院医学薬学研究部(薬学)・薬物治療学研究室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疾患関連分子解析部門3, 公益財団法人東京都医学総合研究所 依存性薬物プロジェクト4, 広島大学医歯薬保健学研究院神経薬理学研究室5, 名城大学薬学部地域医療薬局学講座6 Dept of Pharm Therapy & Neuropharmacol, Fac of Pharm Sci, Grad Sch of Med & Pharm Sci, Univ of Toyama, Toyama, JAPAN,1, Dept of Psy, Osaka Univ Grad Sch of Med.2, Mol Res Cen for Child Mental Develop, Univ Grad Sch of Child Develop, Osaka Univ.3, Addic Sub Pro, Tokyo Metro Inst of Med Sci, Tokyo.4, Dept of Mole Pharm Neuroscience, Inst of Biomedi and Health Sci, Hiroshima Univ.5, Meijo Univ, Nagoya.6 Piccolo (PCLO) regulates the transport of synaptic vesicles. Recently, clinical studies have suggested that a single nucleotide polymorphism rs13438494 in the intron 24 of the Piccolo (PCLO) gene is associated with bipolar disorder in the meta-analysis of GWAS and Piccolo (PCLO) gene expression in the prefronral cortex. In this study, therefore, we have attempted to evaluate the possible functionality of the Piccolo (PCLO) SNP in mechanisms associated with uptake of neuronal transmitters relate to bipolar disorder. To characterize the intronic SNP rs13438494 in the Piccolo (PCLO) gene, we constructed the risk C allele or the non-risk A allele of the SNP plasmids containing exon 24, intron 24 and Exon 25. Plasmid constructs were transiently transfected in SH-SY5Y cells, followed by RT-PCR analysis was done to assess the genetic effect on splicing. The risk C allele and the non-risk A allele constructs displayed a different ratio between the transcripts, indicating that the intronic SNP affect the splicing pattern. We have also reported that Piccolo (PCLO) C2A domain contributes the regulation of METH-induced inhibition of dopamine uptake in dopamine transporter over expressed PC12 cells. We generated the risk C allele and the non-risk A allele plasmids containing C2A domain, and then transfected in cells with dopamine transporter and serotonin transporter followed by DA and 5-HT uptake analysis to clarify the association to bipolar disorder. In the risk C allele plasmid transfected cells, both DA and 5-HT uptakes were altered compared with the non-risk A allele plasmids transfected cells. These results suggest that Piccolo (PCLO) SNP rs13438498 regulates DA and 5-HT uptakes and involves psychiatric disorders including bipolar disorder.	P2-2-232 マンガン造影MRI法を用いたalpha-CaMKIIヘテロノックアウトマウスの脳機能解析 In vivo mapping of brain activity in alpha-CaMKII heterozygous knockout mice using manganese-enhanced magnetic resonance imaging ○服部聡子1,2,3, 米山操4, 齋藤茂芳4, 青木伊知男4, 佐賀恒夫4, 須原哲也2, 樋口真人2, 宮川剛2,3,5 ○Satoko Hattori1,2,3, Misao Yoneyama4, Shigeyoshi Saito4, Ichio Aoki4, Tuneo Saga4, Tetsuya Suhara2, Makoto Higuchi2, Tsuyoshi Miyakawa2,3,5 藤田保健衛生大・総医研・システム医1, 放医研・分子イメージング研・分子神経2, 放医研・分子イメージング研・分子病態4, 生理研・行動・代謝分子解析センター5 Division of Systems Medical Science, ICMS, Fujita Health University1, Molecular Neuroimaging Program, Molecular Imaging Center, NIRS2, JST・CREST3, Diagnostic Imaging Program, Molecular Imaging Center, NIRS4, Center for Genetic Analysis of Behavior, NIPS5 The alpha isoform of calcium/calmodulin-dependent protein kinase II (CaMKII) is abundant in the postsynaptic density, and plays a key role in synaptic plasticity. Alpha-CaMKII heterozygous knockout (HKO) mice exhibit abnormal emotional and aggressive behaviors and impaired cognitive functions, and are proposed as an animal model of psychiatric disorders. Previously, we reported that expressions of immediate early genes induced by foot shock exposure or working memory training were attenuated in the hippocampus, amygdala, and prefrontal cortex of these mice. However, it remains unclear whether the brain activity was reduced in these regions. In this study, to assess regional activity in the brain of alpha-CaMKII HKO mice, we performed in vivo manganese-enhanced MRI (MEMRI) in these mutant mice. The signal intensity of MEMRI is enhanced by functional increases in calcium influx via transport mechanism including Ca2+ channels, and therefore this method could provide images that may reflect the brain activity.Alpha-CaMKII HKO mice exhibited decreased signal intensity in the dentate gyrus, in which almost all neurons were at pseudo-immature status at molecular, morphological and electrophysiological levels in these mutant mice. Analysis of the signal intensity revealed that, in the mutant mice, the activity is increased in the CA1 of hippocampus and the bed nucleus of the stria terminalis, which are known to be involved in cognitive functions and anxiety. In the other regions of brain, there are no significant differences in the signal intensity between genotypes. These results suggest that the brain activity in the regions may be responsible for the dysregulated behaviors, which are similar to symptoms seen in psychiatric disorders.
P2-2-233 トリブチルスズは酸化ストレスによって海馬神経障害を引き起こす Neuronal injury and oxidative stress induced by tributyltin in rat hippocampal cultured slices ○山崎岳1, 石原康宏1, 川見友人1, 石田敦彦1 ○Takeshi Yamazaki1, Yasuhiro Ishihara1, Tomohito Kawami1, Atsuhiko Ishida1 広島大学大学院　総合科学研究科1 Dept Integra Art & Sci, Hiroshima Univ, Higashi-Hiroshima, Japan1 Tributyltin (TBT) has been used as a heat stabilizer, agricultural pesticide and antifouling agents on ships, boats and fish-farming nets; however, the neurotoxicity of TBT has recently become a concern. TBT is suggested to stimulate the generation of reactive oxygen species (ROS) inside cells. The aim of this study was to determine the mechanism of neuronal oxidative injury induced by TBT using rat organotypic hippocampal slice cultures. The treatment of rat hippocampal slices with TBT induced ROS production, lipid peroxidation and cell death. Pretreatment with antioxidants such as superoxide dismutase, catalase or trolox, suppressed the above phenomena induced by TBT, indicating that TBT elicits oxidative stress in hippocampal slices, which causes neuronal cell death. TBT dose-dependently inhibited glutathione S-transferase (GST), but not glutathione peroxidase or glutathione reductase in the rat hippocampus. The treatment of hippocampal slices with TBT decreased the GST activity. Pretreatment with reduced glutathione attenuated the reduction of GST activity and cell death induced by TBT, indicating that the decrease in GST activity by TBT is involved in hippocampal cell death. When hippocampal slices were treated with sulforaphane, the expression and activity of GST were increased. Notably, TBT-induced oxidative stress and cell death were significantly suppressed by pretreatment with sulforaphane. These results indicate that GST inhibition could contribute, at least in part, to the neuronal cell death induced by TBT in hippocampal slices. This study is the first report to show the link between neuronal oxidative injury and the GST inhibition elicited by TBT.

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