一般、大学院生、若手研究者（ポスター）

一般、大学院生、若手研究者（ポスター）神経伝達物質、修飾物質、シナプスの形成、シナプスの成熟、シナプスの可塑性

P-013（1） Disturbance of HPC-1/syntaxin1A gene expression and its CNV cause autistic spectrum disorder 小藤剛史^1,2，藤原智徳²，真田ますみ²，三嶋竜弥²，林優子³，田丸政男⁴，赤川公朗² ¹杏林大学医学部共同研究施設RI部門，²杏林大学医学部細胞生理学，³県立広島大学保健福祉学部附属診療センター小児科，⁴県立広島大学保健福祉学部作業療法学科 It is thought that pathogenesis of human neuropsychological disorder is associated with synaptic dysfunction. HPC-1/syntaxin1A（STX1A）, a neuronal t-SNARE, contributes to neural function in central nervous system by regulating synaptic transmission. Recent studies demonstrated that STX1A gene possibly related with human neuropsychological disorder such as ADHD. Here, we examined if STX1A gene expression is correlated with human autistic spectrum disorder（ASD）by quantitative RT-PCR using blood or saliva samples. We found copy number variation（CNV）of STX1A gene in a part of ASD（6.0%）. Furthermore, we found a wide variation of STX1A mRNA expression in ASD compared to control group, and mean STX1A mRNA amount was higher than that of control group. These observations suggest that STX1A gene expression may be disturbed in a part of ASD. In order to further study if disturbance of STX1A gene expression causes for neuropsychological abnormalities, the behavioral profiles in STX1A gene knockout mice（STX1A-KO）were analyzed. Interestingly, STX1A-KO exhibited unusual behavioral profiles, such as fear memory deficit, attenuation of latent inhibition and impairment of social behavior, which resemble symptoms of human ASD. In addition, these unusual behavioral profiles in STX1A-KO were caused by reduction in release of monoamines and neuropeptides, e.g. DA, 5-HT, and oxytocin, as observed in ASD. Considering with these results, the disturbance of STX1A gene expression and its CNV is highly associated with ASD.		P-014（1） Intranasal administration of［Leu¹¹］-HK-1-derived peptides has the antipruriceptive effect in rats 船橋英樹¹，中山-直野留美²，宮原裕¹，西森利數¹，石田康¹ ¹宮崎大学医学部臨床神経科学講座精神医学分野，²宮崎大学医学部機能制御学講座統合生理学分野 Hemokinin-1（HK-1）is a mammalian tachykinin peptide consisting of 11 amino acids, and the intrathecal administration of HK-1 induces scratching behavior. Recently, it was demonstrated that the pretreatment with［Leu11］-HK-1, in which Met at the C-terminus of HK-1 was replaced by Leu, attenuated scratching induced by intrathecal administration of HK-1. In addition, the pretreatment with［Leu¹¹］-HK-1 reduced the induction of scratching behavior by pruritogens such as histamine and serotonin, suggesting that［Leu¹¹］-HK-1 may have an inhibitory effect on pruriceptive processing. Furthermore, it is believed that replacement of amino acids by D-tryptophan（D-Trp）, prolongs the duration of effective time. Therefore, to clarify the effective duration of［Leu11］-HK-1-derived peptides, the effect of pretreatment with［D-Trp⁷］-［Leu¹¹］-HK-1, ［D-Trp⁹］-［Leu¹¹］-HK-1, ［D-Trp^7,9］-［Leu¹¹］-HK-1 on the induction of scratching behavior by the intrathecal administration of HK-1 and by the intradermal injection of some pruritogens was evaluated. Indeed, the induction of scratching by intrathecal administration of HK-1 and intradermal administration of chloroquine or histamine was significantly suppressed by intranasal pretreatment with［D-Trp⁹］-［Leu¹¹］-HK-1. These results indicate that［Leu¹¹］-HK-1-derived peptides replaced by D-Trp have prolonged antipruriceptive effects in rats pretreated intrathecally or intranasally with these peptides.

P-015（1）幻聴体験の分子メカニズムを考える―抗EGFR抗体、抗VEGF抗体の投与後に一過性の対話性幻聴を呈した一例長岡敦子¹，國井泰人^1,2，松本純弥¹，日野瑞城¹，宮川哲平³，飯田聡³，山崎繁³，矢部博興¹ ¹福島県立医科大学神経精神医学講座，²会津医療センター精神医学講座，³太田綜合病院附属太田西ノ内病院外科近年、統合失調症において免疫・炎症システムが慢性的に変化し、毛細血管が主な構成要素である微小循環の機能障害が生じるという仮説が注目されている。我々は、死後脳を用いて血管新生に重要な上皮成長因子受容体（epidermal growth factor receptor：EGFR）と血管内皮成長因子受容体（vascular epidermal growth factor：VEGFR）のシグナル伝達経路の分子発現について検討し、統合失調症前頭前皮質におけるVEGFR発現量の低下を明らかにした。一方、臨床的にもVEGFのシグナル伝達を阻害する薬剤により認知機能障害、精神病症状の出現が報告されている。今回我々は、抗EGFR抗体、抗VEGF抗体の投与により一過性の対話性幻聴を呈した一例を経験したため報告する。尚、この研究は福島県立医科大学の倫理委員会の承認を得ており、ヘルシンキ宣言に基づいた倫理的原則に則って実施され、発表にあたっては対象者から十分なインフォームド・コンセントを得て、プライバシーに関する守秘義務を遵守し、匿名性の保持に十分な配慮をした。症例は精神疾患の既往のない65歳の男性。X-2年5月、大腸がん術後に抗EGFR抗体を含む化学療法が施行されたところ、複数の女性が自分の悪口を言う声が出現したが、幻聴体験を訴えれば抗がん剤治療が中止されるのという不安から主治医に告げることはなかった。その後がんの進行に伴い、化学療法の内容が変更され、X-1年7月に抗VEGF抗体の投与が開始されたところ、幻聴は脅迫的な内容に変化し恐怖を覚えたため、X年12月に幻聴体験を訴え精神科紹介となった。幻聴体験は抗精神病薬投与により改善され、現在も2週に1回の化学療法を継続している。本例のような幻聴体験は病識保持のため症状があっても訴えない可能性を考え、我々は一定期間内に上記分子標的剤の投与を受けた患者に対して幻聴体験の有無に関する聞き取り調査を行った。本会ではその結果も報告するとともに、本例及び死後脳研究の結果を踏まえて、EGF及びVEGFを介したシグナル伝達を中心に幻聴体験の分子メカニズムを考察する。		P-016（1） Carbon monoxide is essential for Schwann cell responses to peripheral nerve injury オムヒョンソク Kyunghee Univ., Hoegi-dong, Dongdaemun-gu, Seoul, Korea Heme oxygenase（HO；encoded by HMOX genes）is a microsomal enzyme that metabolizes to heme and produces biliverdin, carbon monoxide（CO）, and iron（Fe）protoporphyrin. HMOX genes are expressed by most living organisms including bacteria, algae, plants, insects, and mammals, suggesting that the need for heme catabolism by HO occurred early during evolution. Till date, three isoforms of HO（HO-1, HO-2, and HO-3）have been identified. HO-1 expression is induced ubiquitously in response to oxidative stress, whereas HO-2 is constitutively expressed and not inducible. Previous studies revealed that CO can modulate a variety of physiological processes, including gasotransmitter. Similar to CO, H₂ S is the most recently described gasotransmitter and is essential for Schwann cell responses to peripheral nerve injury. However, the inhibition effect of CO on peripheral nerve injury is still unknown. Thus, we examined role of CO on peripheral nerve injury. First, we visualized stripes at sciatic nerve through explant cultrure, by the use of HO-inhibitor like SnPP（stannum protoporphyrin or tin protoporphyrin）, SnMP（stannum mesoporphyrin or tin mesoporphyrin）which is a strong proof of delayed in wallerian degeneation. Increased HO-1 and HO-2 mRNA expression in injuryed sciatic nerve also support the result of explant culture. Western blotting analysis also demonstrated the upregulated HO-1 and HO-2 expression on the sciatic nerve injuryed side as compared to that of control sample. Immunostained slide of teased nerve fibers also showed the ovoid formation in injuryed sample.Our experimental evidence based upon ex-vivo sciatic nerve explant culture, quantitive RT-PCR and western blotting data, IHC strongly suggest that the inhibition of HO production prevented the process of axonal degradation and demyelination including myelin fragmentation, dedifferentiation, Schwann cell proliferation in vitro. Thus, these results indicate that HO is essential for Schwann cell responses to peripheral nerve injury.

P-017（1） Phldb2, a phosphoinositide mediator, regulates synaptic plasticity through AMPA receptor and CaMKII 謝敏かく^1,2,3,4，八木秀司⁵，猪口徳一⁶，岡雄一郎^4,6，黒田一樹^2,3，深澤有吾^2,3，松崎秀夫^1,4，岩田圭子^1,4，石川保幸⁷，佐藤真^1,4,6 ¹福井大・子どものこころの発達研究センター・脳機能発達研究部門，²福井大・医・脳形態機能学領域，³福井大・ライフサイエンスイノベーションセンター，⁴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，⁵兵庫医科大・医・解剖学・細胞生物学部門，⁶大阪大学大学院・医・解剖学講座，⁷前橋工科大・システム生体工学 Phosphoinositides, such as phosphatidylinositol 3,4,5-triphosphate（PIP₃）, are essential regulators for diverse range of biological events. For synaptic plasticity, involvement of PIP₃ for LTP is reported, yet how they regulate the subsequent molecular machineries mostly remains elusive. We show here that Phldb2, of which PH domain is one most sensitive to PIP₃, controls synaptic plasticity；long-term potentiation（LTP）and long-term depression（LTD）induced in hippocampal slices by high frequency stimulation（HFS）and by low frequency stimulation（LFS）, respectively. Phldb2 bound to AMPA receptor subunits（GluA1 and GluA2）and CaMKII, which plays an essential role in the synaptic plasticity. The AMPA receptor, especially GluA1, accumulation at the postsynaptic membrane reduced in the Phldb2 KO mice. Furthermore, Phldb2 kept an interaction between NMDA receptor and CaMKII, which is critical for synaptic plasticity. The interaction between CaMKII and NR2B was enhanced after PIP₃ stimulation. In conclusion, Phldb2 is a versatile, but is critical mediator for synaptic plasticity through CaMKII and AMPA receptor.		P-018（1） Persistent alterations in the morphology of dendrites in prefrontal cortex neurons following a single administration of ketamine 山本敏文，掛亜希子，山本秀子横浜市大院・生命ナノシステム科学研究科・分子精神薬理学 Subanesthetic doses of ketamine produce psychotic symptoms. Ketamine has been used in animal models of schizophrenia. Recent studies have demonstrated that ketamine produces rapid and long-lasting antidepressant effects. Furthermore, several studies in major depressive disorder have demonstrated structural alterations, such as the decrease in the density of spines and in the number of dendrite branches, of several regions, including the prefrontal cortex（PFC）, hippocampus, and basal ganglia. In the present study, we investigated the morphological alterations after a single administration of ketamine using Golgi-Cox staining. At 1 day or 7 days after the administration of ketamine（0.5-25 mg/kg, i.p.）in male Long-Evans rats（20w）, neuronal morphological changes were estimated in the PFC（Cg1, M1, and M2 regions）, hippocampus（CA1, CA2, CA3, and DG regions）, and nucleus accumbens（nAcc）. In the prefrontal cortex, ketamine produced a rapid and persistent increase in the number of branches and length of dendrites at 1 day after administration in a dose-dependent manner. The increase in the number of branches and spine density was also observed 7 days after a single administration of ketamine in the PFC. On the other hand, in the core and shell regions of nAcc, no significant changes were observed. These results indicate that ketamine increased dendritic branching rapidly and persistently in prefrontal cortex areas. Therefore, the rapid and persistent properties of the morphological changes may be associated with the fast-acting antidepressant effect of ketamine.