神経発達障害 Neurodevelopmental Disorders
P2-1-174 注意欠陥/多動性障害モデルラットSHRの多動、前頭前野モノアミン遊離に対するセロトニン-ノルエピネフリン再取り込み阻害薬の作用 Effects of serotonin-norepinephrine reuptake inhibitors on hyperlocomotion and prefrontal monoamine release in spontaneously hypertensive rats, an animal model of attention-deficit/hyperactivity disorder ○藤田和美1, 梅原真人1, 吾郷由希夫1, 平松直樹1, 田熊一敬1, 松田敏夫1,2 ○Kazumi Fujita1, Masato Umehara1, Yukio Ago1, Naoki Hiramatsu1, Kazuhiro Takuma1, Toshio Matsuda1,2 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 Attention-deficit hyperactivity disorder (ADHD) is one of the most common developmental disorders in children and some symptoms continue until adulthood. Although the etiology of ADHD is not known, catecholamine neurotransmission in the prefrontal cortex plays a key role in the therapeutic actions of drugs for ADHD such as methylphenidate and atomoxetine. Recent clinical studies have shown that the serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs), venlafaxine and duloxetine, effectively treat the core of ADHD symptoms. However, the exact mechanism of the effect is unclear. In this study, we examined the effects of acute treatment with SNRIs on hyperlocomotion and the extracellular levels of monoamines in the prefrontal cortex in spontaneously hypertensive rats (SHR), an animal model of ADHD. Adolescent SHR exhibited greater horizontal locomotor activity in an open-field test than Wister Kyoto (WKY) control rats. The SNRIs, duloxetine and venlafaxine, similar to methylphenidate, reduced hyperlocomotion in SHR. The NE reuptake inhibitors reboxetine also reduced hyperlocomotion in SHR, whereas the selective 5-HT reuptake inhibitor citalopram did not. Microdialysis studies showed that methylphenidate, duloxetine, venlafaxine, and reboxetine increased the extracellular levels of NE and DA in the prefrontal cortex in SHR, but citalopram did not affect prefrontal NE and DA levels. Moreover, the ameliorating effects of methylphenidate and venlafaxine on hyperlocomotion were blocked by idazoxan, an α2-adrenoceptor antagonist, but not by SCH23390, a dopamine-D1 receptor antagonist. These findings suggest that SNRIs, like ADHD drugs, have potential for ameliorating motor abnormality in the SHR model and that the α2-adrenoceptor activation through increasing prefrontal NE levels via NE transporter inhibition plays a key role in the effects of methylphenidate and venlafaxine.	P2-1-175 動物介在活動に基づく自閉症小児のためのロボット介在活動の設計に関する研究 On the design of robot-assisted activities based on animal-assisted activities for children with Autism spectrum disorders ○廣川暢一1, 舟橋厚2, 鈴木健嗣3,4 ○Masakazu Hirokawa1, Atsushi Funahashi2, Kenji Suzuki3,4 筑波大学大学院　システム情報工学研究科1, 愛知県心身障害者コロニー　発達障害研究所2, 筑波大学　サイバニクス研究センター3, 独立行政法人　科学技術振興機構4 Graduate school of Systems and Information Engineering, University of Tsukuba, Tsukuba1, Dept Education and Social Service Inst Developmental Res, Aichi Human Service Center, Kasugai Japan2, Center for Cybernics Research, University of Tsukuba, Tsukuba, Japan3, Japan Science and Technology Agency, Japan4 We report the preliminary experiment of robot-assisted activities(RAA) for children with ASD as a post session of animal-assisted activities(AAA). We have already reported that AAA can make a positive effect for ASD children to have positive social interaction with others and to reduce behavioral problems. The purpose of RAA is aimed at identifying specific behavioral factors of animals that facilitate socially positive behaviors of ASD children, designing the psychoeducational approach to train social skills, and development of robotic system for therapeutic use. Compared to AAA, RAA holds several advantages i) controlling whole behaviors of the robot in order to organize social skill trainings, ii) monitoring and recording children's behaviors and physical interactions using sensors, and iii) characterizing it as an adaptive companion for children with ASD.A small humanoid robot with 70cm height has been used. 5 children diagnosed as ASD and 4 ordinary developed children voluntary participated individually. Each subject have interacted with the robot freely for 10~15 minutes after AAA session. The robot was tele-operated by an experimenter using the control system of the robot which is designed to interact and to respond to the spontaneous action of the child. The other experimenter recorded the facial expression, especially smile, of the child in order to analyze the subject's emotional reactions. Also, the robot's vision and images from the ceiling camera have been recorded for capturing whole session.As a result, none of ASD children showed negative social behaviors when they encountered the robot for the first time even though some of them were afraid of dogs in first few sessions of AAA. Besides, we observed that most of ASD children voluntary showed positive social behaviors to the robot such as shaking hands, eye-contact and helping behavior. That may indicate the robot has a capability to be a significant tool for the treatment of children with ASD.
P2-1-176 動物介在活動中またはロボット介在活動中の自閉症スペクトラム障害児の社会的行動と笑顔の関連について　―笑顔識別インターフェイスを用いた定量的解析と行動評定― Relationship between social behaviors and smiles of a child with Autism Spectrum Disorders during the animal-assisted or robot-assisted activities -behavioral observation and quantitative analysis using a smile detection interface- ○舟橋厚1, , 青木健3, 廣川暢一2, 門根秀樹4, 鈴木健嗣4,5 ○Atsushi Funahashi1, Anna Gruebler2, Takeshi Aoki3, Masakazu Hirokawa2, Hideki Kadone4, Kenji Suzuki4,5 愛知県心身障害者コロニー・発達障害研・教育福祉1, 筑波大院　システム情報工学　知能機能システム人工知能研2, 中部アニマルセラピー協会3, 筑波大学　サイバニクス研究コア4, 科学技術振興機構5 Dept. of Education and Social Service Inst. of Devel. Res. Aichi Human Service Center, Japan1, Dept. of Intelligent Interaction Technologies, Graduate school of Systems and Information Engineering, Univ. of Tsukuba, Tsukuba, Japan2, Cyubu Animal assisted Therapy Association., Nagoya, Japan3, Center for Cybernics Research, Univ. of Tsukuba, Tsukuba, Japan4, Japan Science and Technology Agency, Japan5 We quantitatively measured the smiles of a child with autism spectrum disorder (ASD) with a wearable interface device during animal-assisted activities (AAA) for 7 months and compared the behavior with that of a control of the same age. Then, the subjects participated in the robot-assisted activities (RAA) in the subsequent post-session. The subjects were a 10 year-old boy with ASD and a normal healthy boy of the same age as the control. They voluntarily participated in this study. They comfortably kept wearing the device during the whole experiment (duration of a session is about 30-40 min). The sessions were carried out individually one time every 2 months. The behaviors of the subjects during the AAA and the RAA were video-recorded and coded by the medical examiner (ME). In both subjects, the smiles recognized by the ME during the AAA corresponded with the computer-detected smiles. The positive social behaviors during the AAA increased when the smiles increased in both groups. However, the negative social behaviors during the AAA decreased when the smiles increased in the child with ASD. The child with ASD showed more positive social behaviors related to smiles during the RAA compared with his own positive social behaviors during the AAA. The child with ASD also came closer to the robot than to the animals when he first encountered these stimuli. These findings may suggest that by leading children with ASD into a social environment that may cause smiling, their positive social behaviors may be facilitated and their negative social behaviors may be decreased. It is also suggested that a robot as well as the animal (dogs) can be a useful tool for the children with ASD in order to facilitate their social and communicational behaviors.	P2-1-177 自閉症スペクトラム障害者における聴覚皮質の反応 Cortical response to sound in autism spectrum disorders ○船曳康子1, 村井俊哉1, 十一元三2 ○Yasuko Funabiki1, Toshiya Murai1, Motomi Toichi2 京都大学・医・精神科1, 京都大学・医・人間健康科学2 Dept Psychiatry, Kyoto Univ, Kyoto1, Human Health Science, Kyoto Univ, Kyoto2 Individuals with autism spectrum disorders (ASD) can demonstrate hypersensitivity to sounds, but also show unawareness. Several functional imaging studies have suggested an abnormal response in the auditory cortex, but it is not known whether these subjects have an abnormality in the auditory cortex or just do not listen. We measured changes in blood oxygenated hemoglobin (oxyHb) in the prefrontal and temporal cortices using near-infrared spectroscopy during various listening and ignoring tasks. Here we show that cortical responses to sounds differed not in the auditory but in the prefrontal region between the ASD and control groups. Also, ASD subjects remembered several parts even in the ignoring task, whereas controls did not. The difficulty in attention control may account for the contrary behaviors of hypersensitivity and unawareness to sound in ASD.
P2-1-178 Narrowing down the critical chromosomal regions for neurological anomalies in Down syndrome mouse models Narrowing down the critical chromosomal regions for neurological anomalies in Down syndrome mouse models ○ラボマチュー1, 浅田幸江1, 天野賢治1, 下畑充志1, 山川和弘1 ○Matthieu Raveau1, Sachie Asada1, Kenji Amano1, Atsushi Shimohata1, Kazuhiro Yamakawa1 神経遺伝チーム-　理化学研究所 Brain Science Institute1 Laboratory for Neurogenetics, RIKEN Brain Science Institute1 Down syndrome (DS) in human is caused by the triplication of human chromosome 21 (Hsa21) and is the most common genetic cause of mental retardation (average prevalence: 1 in 750 live births). This gene dosage imbalance affects organogenesis and many physiological functions in which mental retardation is the most striking as it has a fully penetrance. Syntenic regions (i.e. regions carrying the same genes, in the same order and relative orientation) to Hsa21 can be found on mouse chromosomes 16, 17 and 10 (Mmu16, 17 and 10). The main homologous region is located on Mmu16 and represents ~58% of Hsa21. Several mouse models for DS were developed harboring partial trisomies for this region (Ts65Dn/Ts2Cje, Ts1Cje, Ts1Rhr). The largest trisomies (Ts65Dn and Ts1Cje) display anomalies in behavior, physiological functions (LTP), cell function and signaling (vesicular trafficking) whereas shorter duplication in Ts1Rhr shows milder/no impairment for these items. Previous work in our team showed increased lipid peroxidation (Ishihara et al. 2009) as well as adult neurogenesis impairment and enlarged brain ventricles (Ishihara et al. 2010) similar in Ts2Cje (equivalent to Ts65Dn) and Ts1Cje mice leading to the conclusion that Ts1Cje fragment contained the main target gene(s) triggering these anomalies. In the present study we define more precisely the leading regions for these phenotypes through a comparative study between Ts1Cje and Ts1Rhr. We show Ts1Rhr is not sufficient to trigger lipid peroxidation and adult neurogenesis impairments, but is sufficient to cause enlarged brain ventricles. Using subtractive approach by targeting Pcp4 gene to set it back to 2 copies in Ts1Rhr we show its resumption is able to partially rescue ventricular volume anomalies. Our results thus refine the regions of interest for molecular and histological phenotypes in DS mice, reducing the number of potential target genes for further investigations.	P2-1-179 自閉症の顔認知における紡錘状回の活動 Abnormal activation in the fusiform gyrus during face recognition in autism: a pilot study ○小俣圭1, 吉原雄二郎2, 尾内康臣3, 森則夫1,2, 武井教使1 ○Kei Omata1, Yujiro Yoshihara2, Yasuomi Ouchi3, Norio Mori1,2, Noriyoshi Takei1 浜松医科大学　子どものこころの発達研究センター1, 浜松医科大学　精神科2, 浜松医科大学　メディカフォトニクス研究センター　生体機能分子イメージング研究室3 RCCMD, Hamamatsu University School of Medicine1, Dept. Psychiatry, Hamamatsu University School of Medicine2, Dept. Biofunctional Imaging, Medichal Photonics Research Center, Hamamatsu University School of Medicine3 [Background] While autism spectrum disorder (ASD), known as a neurobiological disorder, is now the focus of public attention, the pathogenic mechanism of the disease remains elusive. Alterations in neuron density and neurotransmitters in the cerebral cortex may be ascribed to peculiar information processing developed in ASD. Since abnormal activation is shown to appear in the fusiform gyrus (FFG) that subserves face recognition in autism, we hypothesize that an abnormality of the FFG activation may be due to alteration in the density of neurons and the quantity of neurotransmitters in the FFG. To test this hypothesis, we investigated the brain functions of the FFG using fMRI regarding face recognition processing, and have been examining the concentration of neurotransmitters and chemicals in the FFG using magnetic resonance spectroscopy, which allows us to measure them in the brain tissues in vivo. Here, we preliminarily report some pilot results of fMRI on face recognition processing. [Method] Participants were 16 high-functioning adults with autism and 15 cognitively normal adults. Pictures of faces, houses and patterns were presented in a short block design in terms of one-back task. The participants were asked to press a button when immediate repetition of the previous image was detected. The data were analyzed using SPM. [Results] Face presentation activated not only the middle temporal gyri but also the bilateral posterior FFG in the control group, whereas in the autistic group the brain activity to the face stimuli was found in the middle temporal gyri, not in the FFG. [Discussion] Although the brain chemical MRS study is underway, the current result showing a lack of activation in the FFG against face stimuli in autistic adults may be linked with abnormal or peculiar shift of tissue chemicals including neurotransmitters in the FFG as one important neurophysiology of autism.
P2-1-180 重症度差異のある一卵性双生児レット症候群患者におけるゲノム・エピゲノム比較解析 Epigenomic difference associated with neurodevelopmental discordance of the monozygotic twins with Rett syndrome ○三宅邦夫1, 久保田健夫1 ○Kunio Miyake1, Takeo Kubota1 山梨大学大学院　医学工学総合研究部　環境遺伝医学講座1 Dept of Epigenetic Med, Univ of Yamanashi, Yamanashi1 Rett syndrome is an X-linked neurodevelopmental disorder caused by mutations in a methyl-CpG-binding protein 2 (MECP2) gene. We here report discordant (differences in autistic characteristics, seizure episodes, EEG findings, and ability to perform physical movements) monozygotic twins with Rett syndrome, who shared a mutation in exon 4 of MECP2 (G269AfsX288). A mono-chromosome hybrid assay demonstrated that the mutation occurred in spermatogenesis. The X-chromosome inactivation (XCI) patterns did not differ in lymphocytes, skin fibroblasts, and hair (originated from ectoderm same as neuronal tissue) in the twins. Therefore, we thought that there might be DNA sequence difference between the twins that alter gene expression, and then performed whole genome sequencing and an BeadChip analyses. As a result, we did not find any SNP differences but found 29 differential CNV candidates by these analyses. However, real-time PCR assay failed to confirm CNV difference, suggesting there is no genomic difference between the twins. We then performed a whole genome DNA methylation analysis using a genome microarray method to investigate epigenomic difference between the twins, and found several differential DNA methylation site between them. We identified loci with differential methylation at upstream regions of genes between the twins, including upstream regions of three genes (MKX, CKB, FYN) in which differential DNA methylation was confirmed with a concordant gene expression pattern between the twins. There results suggest that altered DNA methylation statuses of these genes might have some significance in the discordance of the RTT twins.	P2-1-181 産仔マウスの神経前駆細胞の増殖に対する妊娠期ニコチン暴露の影響 Effect of maternal nicotine exposure on proliferation of neuronal progenitor cells in the fetus ○青山雄紀1,2, , 鳥海和也2, 永井拓1, 鍋島俊隆2,3,4, 山田清文1,4 ○Yuki Aoyama1,2, Tursun Alkam2, Kazuya Toriumi2, Taku Nagai1, Toshitaka Nabeshima2,3,4, Kiyofumi Yamada1,4 名古屋大院・医・医療薬学1, 名城大・薬・薬品作用2, 名城大・薬・地域医療薬局3, NPO J-DO 医薬品適正使用推進機構4 Dept. Neuropsychopharmacol. Hosp. Pharm., Nagoya Univ. Grad. Sch. Med., Nagoya, Japan1, Dept. Chem. Pharm., Meijo Univ. Grad. Sch. Pharm., Nagoya, Japan2, Dept. Region. Pharmaceuti. Care Sci., Meijo Univ. Grad. Sch. Pharm., Nagoya, Japan3, Japanese Drug Organi. Appropri. Use Research, Japan4 Tobacco smoking during pregnancy has significant adverse effects on the overall mental quality of offspring. Various nicotine replacement therapies are being alternatively applied to quit smoking during pregnancy. However, the effect of nicotine exposure during pregnancy on cognitive and emotional behaviors in offspring is unclear. Previously, we have demonstrated that maternal nicotine exposure (MNE) during embryonic day 14 to postnatal day 0 (E14-P0) exhibits severe behavioral abnormalities in offspring. In this study, to investigate the effect of MNE on neuronal progenitor cells, we examined neurochemical analysis in the developing fetus. The offspring received MNE exhibits cognitive and emotional deficits in fear conditioning test and latent inhibition test in adulthood. On the migration assay using 5-bromo-2-deoxyuridine (BrdU), the BrdU positive cells in mice that received MNE were distributed normally with an inside-out pattern on P7, and there were no significant changes in the distribution pattern as compared with control mice. However, the density of BrdU-positive cells labeled on the E14.5 and E15.5 was significantly decreased by MNE, and persisted until adulthood. The reduction of BrdU-positive cell density was evident immediately 30 min after the BrdU administration in mice that received MNE. These results suggested MNE impaired proliferation of neuronal progenitor cells, but not the neuronal migration, which may be involved in the MNE-induced behavioral abnormalities in adulthood.
P2-1-182 神経組織におけるA2BP1の生化学的、形態学的な特性評価 Biochemical and morphological characterization of A2BP1 in the neuronal tissue ○浜田奈々子1, 伊東秀記1, 岩本郁子1, 水野誠1, 森下理香1, 稲熊裕1田畑秀典1, 永田浩一1 ○Nanako Hamada1, Hidenori Ito1, Ikuko Iwamoto1, Makoto Mizuno1, Rika Morishita1, Yutaka Inaguma1, Sachiyo Kawamoto2, Hidenori Tabata1, Koichi Nagata1 愛知県心身障害者コロニー発達障害研究所 神経制御学部1 Dept Mol Neurobiol, Inst for Dev Res, Aichi Human Service Center1, Laboratory of Molecular Cardiology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, USA2 Background : Ataxin-2-binding protein 1 (A2BP1), which is also termed FOX1 or RBFOX1, is considered to regulate alternative splicing of important neuronal transcripts and has been implicated in a variety of neurological/developmental disorders. In this study, we prepared a specific antibody against A2BP1, anti-A2BP1, and carried out biochemical and morphological analyses of A2BP1 in rat and mouse neuronal tissues.Results : We prepared a rabbit polyclonal antibody, anti-A2BP1, against full length of mouse A2BP1-A016 isoform, and affinity-purified it. Specificity of the antibody was confirmed with COS7 cell lysates expressing Myc-A2BP1. Anti-A2BP1 recognized both A016 and A030 isoforms in western blotting and detected endogenous A2BP1 in rodent brain tissues during developmental stages. Biochemical fractionation clarified that A2BP1 with ~60 kDa and ~50 kDa were relatively enriched in the synaptosomal and postsynaptic density fractions, respectively. In immunohistochemical analyses, A2BP1 was detected mainly in the nucleus and weakly in the cell body and dendrites of excitatory neurons in rodent cerebral cortices. In contrast, A2BP1 was not observed in mitotically active progenitor cells in the developing cortices. We then performed immunofluorescence analyses using primary cultured rat hippocampal neurons. In immature 3div neurons, A2BP1 was evenly expressed in the soma, axons and dendrites. Then, as differentiation advances, A2BP1 distribution gradually changed and it came to be enriched in the nucleus. Interestingly, A2BP1 was also observed adjacent to a presynaptic protein, synaptophysin, and a postsynaptic protein, PSD-95, in 20 div neurons.Conclusion : In this study, we carried out biochemical and morphological analyses of A2BP1 by the use of a homemade antibody. The results obtained suggest the role of A2BP1 in the nucleus and near excitatory synapses of differentiated neurons.	P2-1-183 農薬ネオニコチノイド曝露によるラット新生仔小脳培養の遺伝子発現の撹乱―ADHDなど発達障害発症の危険因子としての可能性― Exposure of neonicotinoid pesticide, imidacloprid and acetamiprid, disrupts gene expression profiles in cerebellar cultures from neonatal rats.-Possible risk factors for developmental disorders like ADHD- ○木村-黒田純子1, 小牟田縁1, 黒田洋一郎4, 西藤泰昌2, 林雅晴1,3 ○Junko Kimura-Kuroda1, Yukari Komuta1, Yoichiro Kuroda4, Yasumasa Nishito2, Masaharu Hayashi1,3 公財　東京都医学総合研究所　脳発達・神経再生研究分野1, 公財　東京都医学総合研究所　基盤技術研究センター2, 公財　東京都医学総合研究所　こどもの脳プロジェクト3, 環境脳神経科学情報センター4 Dept Brain Development & Neural Regeneration, Tokyo Metro Inst of Medical Science, Tokyo1, Basic Tech Res Center, Tokyo Metro Inst of Medical Science2, Mental Development Project, Tokyo Metro Inst of Medical Science3, Environmental Neuroscience Information Center4 Imidacloprid (IMI) and acetamiprid (ACE) belong to a new class of neonicotinoid pesticides, which are used widely in the world to protect crops from pest insects and domestic animals from fleas. They act as agonists on nicotinic acetylcholine receptors (nAChRs) and their high toxicities to insects are well established, but their effects on mammalian nAChRs remain to be elucidated. Many types of nAChRs exist in mammals and are important for not only neurotransmission, but also immune system and especially normal brain development. Previously we reported that ACE, IMI, and nicotine exert similar excitatory effects on rat cerebellar neurons at concentrations greater than 1 μM (PLoS ONE 2012). In this study, we examined gene expressions of rat neonatal cerebellar cells cultured for two weeks in the absence or presence of IMI, ACE, or nicotine at concentrations of 1 or 10 μM by DNA microarray (Agilent Whole Rat Genome Ver.3.0) and analytical software (GeneSpring GX, 12.1, Agilent). From a total of 30,367 genes in the DNA array, significant signals of 19,977 mRNAs were detected. Compared with the control culture, 1,370 genes (1 μM) and 1,014 genes (10 μM) were up- or down-regulated at least twofold in ACE, IMI, or nicotine-treated cultures, and they included many genes which are important for synapse formation and brain development. Among these genes, 272 genes (1 μM) and 157 genes (10 μM) were common to ACE, IMI, and nicotine-treated cultures. Therefore, it is possible that neonicotinoids adversely affect the developing mammalian nervous system, as is known to occur with nicotine, a risk factor for developmental disorders including attention deficit/hyperactivity disorder (ADHD).
P2-1-184 胎生期MAM投与によるADHDおよび統合失調症モデルラットの新生児期での反射感覚系および離乳後期での活動性の分析 An analysis of reflex during neonatal period and activity during post-weaning period in AD/HD and schizophrenia model rats induced by prenatal methylazoxymethanol (MAM) treatment ○杉岡幸三1, 高瀬堅吉2, 薛富義3 ○Kozo Sugioka1, Kenkichi Takase2, Tomiyoshi Setsu3 姫路獨協大・医療保健・こども保健・発達神経行動科学・機能形態学1, 東邦大・医・解剖学2, 神戸大院・医・生理学・細胞生物学・神経発生学3 Dept Child Health & Care, Facul Health Care Sci, Himeji Dokkyo Univ, Himeji, Japan1, Dept Anat, Sch Med, Toho Univ, Tokyo, Japan2, Dept Physiol & Cell Biol, Kobe Univ Grad Sch Med, Kobe, Japan3 Pregnant rats were injected with saline (Control) or 25 mg/kg methylazoxymethanol (MAM) on day 15 or 17 of pregnancy (the M15 and M17 groups, respectively). We consider the M17 rat as an AD/HD model rat and the M17 rat as a schizophrenia model rat. Male and female offspring were subjected to reflex tests (surface righting and negative geotaxis) during the pre-weaning period and open-field test during the post-weaning period. After completing another behavioral examinations conducted during adult period, the brains were removed and weighed. The brain weight differed significantly among the 3 groups (75% and 93%, for the M15 and M17 groups, respectively, of the brain weight of the Control). As for the surface righting, the mean median latencies in the M15 (Day 3) and M17 Groups (Day 3 & 4) were significantly longer than that in the Control. As for the negative geotaxis, the mean latencies in both MAM groups (especially in the M15 group) were significantly longer than that in the Control. As for the open-field activity, the male M17 group showed hypoactive tendency on the weaning day (postnatal 21-day). Although the open-field activity on postnatal 28- day was not different among 3 groups, that on postnatal 35-day was significantly decreased in both male MAM groups. The open-field activity in female rats was not different among 3 groups on postnatal 21- and 28-day, but was significantly different among 3 groups on postnatal 35-day (M17 Group showed hypoactive tendency). These behavioral alterations were discussed in relation to findings as for brain histological observations, in which the M15 rat had morphological abnormalities of the hippocampus (disruption of the CA1 pyramidal layer, ectopic neuron mass and double layering of the mossy fiber), and the M17 rat had scattered and degenerated neurons of the 2nd layer of the cortex and pyknosis-like neuron mass of the cingulate and parietal cortices. This work was supported by KAKENHI(22610024).	P2-1-185 胎仔期バルプロ酸曝露マウスの示す認知機能障害は成体期におけるバルプロ酸および酪酸の慢性投与により改善される Paradoxical effects of HDAC inhibitors on learning and memory in the autism mouse model ○高野恵利加1, 片岡駿介1, 原雄大1, 前田優子1, 吾郷由希夫1, 田熊一敞1, 松田敏夫1,2 ○Erika Takano1, Shunsuke Kataoka1, Yuta Hara1, Yuko Maeda1, Yukio Ago1, Kazuhiro Takuma1, Toshio Matsuda1,2 大阪大院・薬・薬物治療1, 大阪大院・5大学連合小児発達学2 Lab. of Medicinal Pharmacol., Grad. Sch. of Pharmaceut. Sci., Osaka Univ., Suita, Osaka1, Unit-Grad. Sch. of Child Dev., Osaka Univ., Suita, Osaka2 Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by deficits in communication, impaired social interaction, and repetitive or restricted interests and behaviors. The epidemiological studies suggest the importance of environmental factors during early life including the fetal period, in the etiology of ASD. Sodium valproate (VPA) is a major antiepileptic drug and for the therapy of bipolar disorders. However, fetal exposure to VPA has been associated with ASD in the offspring. We have recently showed that mice exposed to VPA on embryonic day 12.5 express ASD-like behaviors, such as social interaction impairment and anxiety-like behavior (Kataoka et al., Int J Neuropsychopharmacol. 2013). VPA-induced social interaction deficits were observed in male but not female offspring, and the sex-dependent social interaction deficits might be due to VPA-induced morphological abnormalities in the somatosensory cortex (Hara et al., J Pharmacol Sci, 2012). This study revealed that the VPA-treated mice showed the long-term recognition memory impairment, another ASD-like behavioral abnormality, in the novel object recognition test at 8 weeks old. The effect of VPA was mimicked by fetal exposure to other HDAC inhibitors, sodium n-butyrate (SB) and trichostatin A, but not valpromide lacking histone deacetylase (HDAC) inhibition activity. When the VPA-treated mice were administered by VPA and SB after 4 weeks old for 5 weeks, they did not show the long-term recognition memory deficits. In agreement with behavioral analysis, the VPA-treated mice showed a decrease in dendritic spine density in the hippocampal CA1 regions, and this effect was blocked by the chronic administration with VPA and SB. These results suggest that prenatal VPA induces cognitive impairment and a decrease in dendritic spine density by HDAC inhibition and these effects are blocked by chronic administration of HDAC inhibitors after development.
P2-1-186 精神遅滞関連因子Xpnは,PC12細胞において細胞間・細胞-基質接着に影響し細胞移動を制御する Mental retardation- related molecule, Xpn regulates cell-cell and cell-matrix adhesion and migration in PC12 cells ○馬込卓弥1, 服部剛志2, 谷口学3, 松崎伸介1,3,4, 山田浩平1,4, 高村明孝1,4, 石川淑子1, 遠山正彌1,5, 片山泰一1 ○Takuya Magome1, Tsuyoshi Hattori2, Manabu Taniguchi3, Shinsuke Matsuzaki1,3,4, Kouhei Yamada1,4, Hironori Takamura1,4, Toshiko Ishikawa1, Masaya Tohyama1,5, Taiichi Katayama1 大阪大学大学院　連合小児発達学研究科　分子生物遺伝学1, 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2, 大阪大学大学院医学系研究科神経機能形態学講座3, 大阪大学大学院　連合小児発達学研究科　付属子どものこころの分子統御機構研究センター4, 大阪府立病院機構5 Dept.Molecular Brain Sci., United Graduate School of Child Development, Osaka Univ. School of Medicine, Osaka, Japan1, Dept.of Molecular Neuropsychiatry, Graduate School of Medicine, Osaka Univ., Osaka, Japan2, Dept.of Anatomy and Neuroscience, Graduate School of Medicine, Osaka Univ., Osaka, Japan3, Molecular Research Center for Children's Mental Development, Osaka Univ., Osaka, Japan4, Osaka Prefectural Hospital Organization, Osaka, Japan5 Mental retardation affects 2-3% of the human population and some of these cases are genetically identified. KIAA2022 is one of the responsible genes for X-linked mental retardation (XLMR) in humans. So far, we have revealed that depletion of KIAA2022 inhibited neurite outgrowth of PC12 cells, indicating that the gene participated in neurite extension. Thus, we termed KIAA2022 as an XLMR protein related to neurite extension (Xpn). Furthermore, using the mouse brain and ontogenetic analysis of Xpn by real-time PCR, we demonstrated that Xpn is expressed transiently during the late embryonic and perinatal stages. However, the functional role of Xpn still remains unclear. Here, we show that Xpn regulates cell-cell and cell-matrix adhesion and migration in PC12 cells, using knocked-down and overexpression of Xpn.

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