Poster

Poster 20 Schizophrenia 3 ポスター 20 統合失調症3

P20-1 Evaluation of dopamine D3 receptor occupancy by blonanserin using [11C]-(+)-PHNO [11C]-（+）-PHNOを用いたblonanserinによるドパミンD3受容体占有率の評価 Sakayori Takeshi（坂寄健），キムウーチャン，野上毅，舘野周，大久保善朗 Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan 【BACKGROUND】Blockade of D3 receptor has been suggested as a possible medication for schizophrenia. However, previous PET studies reported that antipsychotics occupied D3 receptor moderately less than D2 receptor. Here we evaluated the effect of blonanserin on D2 and D3 receptors in schizophrenic patients with PET examination using [11C]-(+)-PHNO.　【METHODS】Thirteen patients with schizophrenia (aged 20 - 70 years) participated in this study. Seven of them had PET scans while taking olanzapine (OLZ) and while taking blonanserin (BNS), 3 had only 1 scan with OLZ, and 3 had only 1 scan with BNS. Head MRI was performed to set the region of interest (ROI). We defined the caudate and putamen as D2-rich regions, the substantia nigra and globus pallidus as D3-rich regions, and the cerebellum as reference region. Receptor binding potential (BP) was calculated by PMOD 3.3 and simplified reference tissue method. The BP values were compared with previously reported BP values of 6 healthy subjects. Dopamine receptor occupancies in each of the ROIs were calculated from the BP values. 【Results】The mean occupancies by olanzapine (average 10.7 mg / day) were: caudate nucleus 32.5%, putamen 26.3%, globus pallidus -35.8%, substantia nigra -112.8%. The mean occupancies by blonanserin (average 12.8 mg / day) were: caudate nucleus 61.0%, putamen 55.5%, globus pallidus 48.8%, substantia nigra 34.0%. 【Discussion】In patients with schizophrenia, olanzapine well occupied the dopamine D2 receptor, but occupancy of the dopamine D3 receptor was much less. On the other hand, blonanserin occupied D3 receptor to the same degree as D2 receptor. From this, it was considered that blonanserin, as opposed to olanzapine, works well on D3 receptor.		P20-2 Maternal immune activation by poly I:C alter synaptic inputs in CA1 hippocampus in offspring during development poly I:Cによる母体免疫活性化は発達中の仔の海馬CA1領域のシナプス伝達に影響を与える Yoshino Hiroki（芳野浩樹）¹，中川恵樹¹，小川陽一²，山室和彦¹，法山良信¹，牧之段学¹，山下勝幸³，齋藤康彦²，岸本年史¹ ¹Department of Psychiatry, Nara Medical University ²Department of Physiology 1 ³International University of Health and Welfare Background:Maternal infection is a risk factor of developmental disorder, such as schizophreniaand autism. Our previous study showed that maternal immune activation of mouse bypolyriboinosinic-polyribocytidilic acid (poly I:C) reduced mRNA and protein of myelin basic proteinand delayed myelination in hippocampal CA1 area at early postnatal period and impairedsensorimotor gating tested by prepulse inhibition in adulthood. But it is not known about howmaternal immune activation physiologically affects hippocampal neuronal activity.Methods:We electrophysiologically investigated the influence on synaptic transmission of mouse offspringhippocampal CA1 pyramidal cells by prenatal poly I:C treatment of dam with whole cell patch-clamprecordings from brain slices. The recordings were done at two developmental periods, earlypostnatal period (postnatal day 0 -15) and adulthood (postnatal day 49-70)Results:The poly I:C treatment decreased excitatory synaptic inputs and inversely increasedinhibitory (GABAergic) synaptic inputs onto CA1 pyramidal cell in offspring adulthood. Even in early postnatal period, we found that prenatal poly I:C treatment of dam also reduced excitatory synaptic inputs in offspring CA1 pyramidal cell, and potentially increased GABAergic synaptic inputs, which was uncovered by high potassium-induced neuronal activation.Conclusions:Maternal immune activation developmentally reduces excitatory / inhibitory balanceof off spring hippocampal neuronal circuits from an early postnatal period to adulthood, which could result in net inhibition and poor functional organization and integration of hippocampal circuits

P20-3 DNA methylation profiling using the brain of neonatal poly(I:C) marmoset model 新生児Poly（I:C）投与マーモセットモデル前頭前野組織を用いたDNAメチル化プロフィール解析 Murata Yui（村田唯）¹，上田順子²，文東美紀¹，大西新³，葛西秀俊⁴，池亀天平⁵，趙治磊⁵，神出誠一郎⁵，饗場篤⁴，須原哲也³，笠井清登⁵，加藤忠史²，岩本和也¹ ¹Dept. Molecular Brain Science, Kumamoto Univ, Kumamoto, Japan ²Lab. Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Saitama, Japan ³Dept. Functional Brain Imaging, NIRS, QST, Chiba, Japan ⁴Lab. Animal Resources, Center for Disease Biol. & Integrative Med., Grad. School of Med., Univ. of Tokyo, Tokyo, Japan ⁵Dept. Neuropsychiatry, Univ. of Tokyo, Tokyo, Japan Poly(I:C), a synthetic analogue of double-stranded RNA, is widely used to produce an animal model of psychiatric disorders. Pregnant mothers injected with poly(I:C) develop maternal immune activation, and offspring generally show neurodevelopmental alterations and abnormal behaviors. Currently, rodents are mainly used in model production, however, nonhuman primates would be beneficial for modelling psychiatric disorders. Therefore, we are developing the maternal poly(I:C) injection model using common marmoset.Here we report the DNA methylation analysis of brain and blood samples of neonatal marmoset born from poly(I:C) injected dams. To profile DNA methylation in the marmoset samples, we developed a bioinformatic pipeline to utilize the commercially available beadchip arrays, originally designed to analyze human genome (Ueda, Murata et al, 2017). Pregnant marmosets (E40~44: “early”, or E80~84: “late”) were injected with poly(I:C) for 5 consecutive days. Genomic DNA was extracted from tissues derived from newborn marmoset, and analyzed DNA methylation status with the arrays. We found that poly(I:C) injection at the early and late developmental periods showed common DNA methylation changes in the genes related to development in brains of newborn marmoset. In addition, injection at the late developmental period showed DNA methylation changes in neural development and behavior-related genes. Notably, some of the DNA methylation changes in the brain were also detected in blood samples, suggesting the possibility of development of epigenetic markers. These results will contribute to understand the molecular basis of altered gene expressions during early brain development in this model.		P20-4 Whole exome sequencing of 14 schizophrenia multiplex families in Japan 統合失調症多発家系14家系の全エクソーム解析による疾患関連一塩基変異の探索 Toyama Miho（遠山美穂）¹，高崎悠登¹，Aleksic Branko¹，荻朋男²，尾崎紀夫¹ ¹Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan ²Department of Genetics, Nagoya University Research Institute of Environmental Medicine, Nagoya, Japan Background Numerous studies exploring genetic risk factors for schizophrenia have been done to elucidate the pathogenesis of this condition, because of its high heritability. Most of studies exploring disease-associated rare variants utilizing Whole Exome Sequencing (WES) have been conducted focusing on de novo genetic variants. However, the role of transmitted variants in the onset of schizophrenia still remains unclear. Thus, WES in multiplex families would be a prospective solution to identify disease-associated rare variants shared among patients. Materials and Methods We performed WES study using 29 patients with schizophrenia, one patient with obsessive compulsive disorder and nine healthy controls from 14 schizophrenia multiplex families in Japan. We focused on rare single nucleotide variants (SNVs) with allele frequency (AF) ≦ 1% among several databases considering difference of AF among them. SNVs shared only within patients as well as de novo SNVs in highly intolerant genes with percentile residual variation intolerance score ≦ 25% were selected as the final results. Results and Discussions We identified 209 transmitted mutations including two homozygous SNVs in CNTN6 and MAOB genes, and three de novo SNVs in CACNA1C, ODC1 and BRD4 genes. Furthermore, eight genes in which we detected candidate variants, including CNTN6 and CACNA1C, have been recurrently reported to have rare variants associated with developmental disabilities and psychiatric disorders. Our results suggested that these genes might be strongly related to pathogenicity of common symptoms among those disorders. Ethics Approval This study was approved by the Ethics Committees of Nagoya University Graduate School of Medicine. Written informed consent was obtained from all individual participants.

P20-5 METH-induced behavioral deficits and morphological changes of accumbal neurons in an animal model for schizophrenia 統合失調症モデル側坐核ニューロンの形態学的およびメタンフェタミン反応性の変化 Hada Kazuhiro（羽田和弘）¹，永井拓¹，伊藤教道¹，祖父江顕¹，Wulaer Bolati^1,3，森大輔²，久島周²，鍋島俊隆^3,4，尾崎紀夫²，山田清文¹ ¹Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine ²Department of Psychiatry, Graduate School of Medicine, Nagoya University ³Advanced Diagnostic System Research Laboratory Fujita Health University, Graduate School of Health Sciences ⁴Aino University Schizophrenia is a severe mental illness that affects about 1% of the population. Genetic and environmental factors contribute to the risk for schizophrenia. However, the exact pathoetiology remains unclear and no effective treatment has been available yet. We previously found rare variant of Rho GTPase-activating protein 10 (ARHGAP10) gene in Japanese schizophrenia patient, and generated ARHGAP10 mice carrying similar mutations found in the patient. In the present study, we examined spatio-temporal expression level of ARHGAP10 mRNA in the brain of mice. The expression levels of ARHGAP10 mRNA showed higher levels in the striatum (Str) and nucleus accumbens (NAc) than those in other brain regions. To evaluate the behavior performances of the ARHGAP10 mice, we performed open field test, elevated plus maze test, Y-maze test, locomotor activity, novel object recognition test, social interaction test, pre-pulse inhibition test, fear conditioning test, rota-rod test, methamphetamine (METH)-induced hyperlocomotion and visual discrimination task. ARHGAP10 mice showed an increase in anxiety level. ARHGAP10 mice also manifested potentiation of hyperlocomotion and discriminative impairment induced by METH treatment. Morphological analysis revealed that METH-treated ARHGAP10 mice showed higher number of c-Fos-positive-cell in the NAc core than those in wild-type littermates. Golgi stain indicated that ARHGAP10 mice showed an increase in neuronal complexity and spine density in the NAc core compared to the WT mice. Taken together, these results suggest that the behavioral abnormalities observed in ARHGAP10 mice may associated with the altered function in NAc neurons and morphological changes.		P20-6 Relationship between concentrations of glutamate in caudate and abilities of musical beat perception and production in schizophrenia 統合失調症におけるグルタミン酸濃度異常と音楽知覚・生成能力異常の関係性の検討 Honda Shiori（本多栞）¹，垂水良介^2,3，越智涼⁴，松下佳鈴⁴，津川幸子²，加藤彩⁴，野田賀大²，中島振一郎²，三村將²，藤井進也⁴ ¹Graduate School of Media and Governance, Keio University , Kanagawa, Japan ²Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan ³Seikei-Kai Komagino ,Hospital ,Tokyo,Japan ⁴Faculty of Environment and Information Studies, Keio University, Fujisawa, Kanagawa, Japan Background: Glutamatergic dysfunction in the basal ganglia may contribute to cognitive impairments in schizophrenia. Previous studies have shown that the basal ganglia plays a central role in processing a rhythm and a beat while listening to music. However, the relationship between glutamatergic system and the beat processing ability remains unknown. Here we aimed to investigate the relationship between glutamate levels in the caudate and the beat processing abilities in patients with schizophrenia. Method: Forty-three patients with schizophrenia participated in the study. Glutamatergic neurometabolite levels in the right caudate were assessed with 3T 1H-MRS (PRESS, TE=35ms). To assess beat processing abilities, we employed the Harvard Beat Assessment Test (H-BAT). Partial correlation analyses were performed to examine relationships among the H-BAT scores and the glutamatergic neurometabolite levels by controlling for severity of extrapyramidal symptoms measured with the Simpson-Angus Scale and chlorpromazine equivalent dose. The study was conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects. Results: There were correlations between the H-BAT scores and the Glutamate levels (p < 0.05). The H-BAT subtest scores assessing the abilities to produce meter and to perceive temporal change, were correlated with the glutamate levels in the caudate (r = - 0.39, p = 0.02; r = - 0.36, p=0.04, respectively). Conclusion: We found the link between the beat processing ability and the glutamatergic level in the caudate in patients with schizophrenia. The glutamatergic dysfunction may relate to beat processing impairments in schizophrenia.

P20-7 Neurocognitive Deficits in anorexia nervosa and schizophrenia by using the MATRICS Consensus Cognitive Battery 包括的認知機能テストバッテリーを用いた神経性やせ症と統合失調症における認知機能障害の検討 Chen Runshu（陳潤舒）¹，田宮裕子¹，大内淳¹，宮澤志保²，岩本直子¹，住吉チカ³，住吉太幹⁴，大森哲郎⁵，中込和幸⁴，兼田康宏⁶，曽良一郎¹ ¹Dept. of Psych. Med., Univ. of Kobe ²Department of Biological Psychiatry, Tohoku University Graduate School of Medicine, Sendai, Japan ³Faculty of Human Development and Culture, Fukushima University, Fukushima, Japan ⁴National Center of Neurology and Psychiatry, Tokyo, Japan ⁵Department of Psychiatry, Tokushima University Graduate School of Medicine, Tokushima, Japan ⁶Iwaki Clinic, Tokushima, Japan Objectives:Schizophrenia is acknowledged as inefficient functioning across a wide range;whereas the previous study showed that Anorexia Nervosa is associated with cognitive dysfunction, including that the patients tend to perform poorly in big picture which was attributed to the obsessiveness with details (central coherence deficits) and have difficulties in coping with set shifting tasks, etc. To perform a comprehensive assessment and comparative investigation among AN-R(Restricting),AN-BP(Binge-eating/Purging),schizophrenia and healthy controls.Methods:We applied the MCCB to evaluate the cognitive function for 22 patients with AN-R and 18 patients with AN-BP and 42 patients with schizophrenia and 69 healthy controls. Results:The patients with AN-R showed the same degree cognitive dysfunction in working memory, visual learning, Reasoning and Problem solving and social cognition domains; In addition to these areas, the patients with AN-BP also showed the same degree cognitive dysfunction in Speed of processing, domains as compared with Schizophrenia patients.Conclusion:This study showed that the same extent impairments in a certain neurocognitive domain were found in AN patients compared to Schizophrenia patients. Furthermore, the results also showed that is the same degree cognitive dysfunction in visual learning and social cognition domains for both subtypes of AN patients who compared to schizophrenia patients.The finding suggested that it would be important to introduce targeting treatment for characteristics in visual learning and social cognition domains.The study was conducted according to the standards of the Declaration of Helsinki and was approved by the Kobe University Hospital Ethics Committee and written consent was obtained from all participants.		P20-8 Correlation analysis between mismatch negativity and gamma-oscillation in early stages of schizophrenia 統合失調症の早期段階におけるミスマッチ陰性電位とガンマオシレーションとの相関解析 Koshiyama Daisuke（越山太輔），切原賢治，多田真理子，永井達哉，藤岡真生，臼井香，小池進介，管心，荒木剛，笠井清登 Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo The altered structure and function of the auditory cortex is one of the core features of the brain pathophysiology of schizophrenia. Animal studies have suggested that N-methyl-D-aspartate receptor (NMDAR) dysfunction causes impairment in gamma-aminobutyric acid (GABA)-ergic interneurons. The NMDAR and GABAergic-interneuron functions in the auditory cortex may be indexed by mismatch negativity (MMN) and auditory steady-state gamma-band response (ASSR), respectively. However, no previous studies have tested the hypothesis of an abnormal association between MMN and gamma-band ASSR in the same patients to identify the in vivo evidence of NMDAR-GABA association during the early stages of psychosis. Participants were individuals with recent-onset schizophrenia (ROSZ; N = 21), ultra-high risk (UHR; N = 27), and healthy controls (HCs; N = 24). Written informed consent was obtained from each subject before participation. The Research Ethics Committee of the Faculty of Medicine at the University of Tokyo approved this study (approval No. 629 and 2226). The MMN amplitude was significantly impaired in ROSZ and UHR compared with HCs. The intertrial phase coherence (ITC) index of gamma-band ASSR was significantly reduced in ROSZ compared with HCs and UHR. The event-related spectral perturbation (ERSP) index of gamma-band ASSR was significantly smaller in ROSZ compared with HCs. The MMN amplitude was significantly correlated with the ITC in ROSZ (r = -0.69, p < 0.001). These findings provide the first in vivo evidence that an abnormal association of the electrophysiological indices of NMDAR and GABA dysfunctions may be present in recent-onset schizophrenia.