一般口演
統合失調症
Schizophrenia
座長：武井 延之（新潟大学 脳研究所 基礎神経科学部門 分子神経生物学分野） |
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| 2022年7月2日 17:10～17:25 沖縄コンベンションセンター 会議場B3・4 第6会場
3O06e2-01
経頭蓋直流刺激のメカニズムの基礎研究におけるエビデンス；系統的レビューによる検討
Preclinical Evidence for the Mechanisms of Transcranial Direct Current Stimulation in the Treatment of Psychiatric Disorders; A Systematic Review
*山田 悠至(1)、住吉 太幹(2)
1. 国立研究開発法人 国立精神・神経医療研究センター病院、2. 国立研究開発法人 国立精神・神経医療研究センター精神保健研究所
*Yuji Yamada(1), Tomiki Sumiyoshi(2)
1. National Center of Neurology and Psychiatry, 2. National Center of Neurology and Psychiatry
Keyword: transcranial direct current stimulation, tDCS, non-invasive brain stimulation
Backgrounds. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique for the treatment of several psychiatric disorders, eg, mood disorders and schizophrenia. Although tDCS provides a promising approach, its neurobiological mechanisms remain to be explored. Objectives. To provide a systematic review of animal studies, and consider how tDCS ameliorates psychiatric symptoms. Methods. A literature search was conducted on English articles identified by PubMed. We defined the inclusion criteria as follows: (1) articles published from the original data; (2) experimental studies in animals; (3) studies delivering direct current transcranially, ie, positioning electrodes onto the skull. Results. 138 papers met the inclusion criteria. 62 papers deal with model animals without any dysfunctions, followed by 52 papers for neurological disorder models, and 12 for psychiatric disorder models. The most studied category of functional areas is neurocognition, followed by motor functions and pain. These studies overall suggest the role for the late long-term potentiation (LTP) via. anodal stimulation in the therapeutic effects of tDCS. Conclusions. Anodal tDCS may provide a novel therapeutic strategy to particularly enhance neurocognition in psychiatric disorders. Its mechanisms are likely to involve facilitation of the late LTP. | | 2022年7月2日 17:25～17:40 沖縄コンベンションセンター 会議場B3・4 第6会場
3O06e2-02
SEP-363856の有効性は｢統合失調症のＤ-細胞仮説｣を検証する
Efficacy of SEP-363856 verifies "D-cell hypothesis of schizophrenia"
*池本 桂子(1)
1. いわき市医療センター
*Keiko Ikemoto(1)
1. Iwaki City Medical Center
Keyword: schizophrenia, TAAR1, SEP-363856, trace amine
The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. The compound is trace amine-associated receptor 1 (TAAR1) full agonist and also 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), a neuroleptic acting site, of human brains, though failed to find in the homologous area of monkey brains. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high quality antibodies against monoamine-related substances, was applied. As the number of D-neurons in immunostained specimens reduced according to post-mortem period to fixation (PMI), brains with PMI less than 8 hours were used for quantification. The number of D-neuron in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p<0.05) in Acc. I proposed “D-cell hypothesis of schizophrenia”, that NSC dysfunction-based D-neuron reduction is cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, progressive pathophysiology and prospectiveness of TAAR1 medicinal chemistry, emphasizing importance of D-neuron. The efficacy of SEP-363856 verified "D-cell hypothesis of schizophrenia". | | 2022年7月2日 17:40～17:55 沖縄コンベンションセンター 会議場B3・4 第6会場
3O06e2-03
統合失調症患者とそのモデル動物の聴覚野におけるEGR1/zif268の発現変化
Elevation of EGR1/zif268 in the auditory cortex of patients with schizophrenia and its animal model
*岩倉 百合子(1,2)、川原 玲香(3)、喜田 聡(4,5)、外山 英和(2)、Ramil Gabdulkhaev(6)、高橋 均(6)、國井 泰人(7,8)、日野 瑞城(7,8)、長岡 敦子(7)、泉 竜太(7)、宍戸 理紗(7)、染矢 俊幸(9)、矢部 博興(7)、柿田 明美(6)、那波 宏之(10,2)
1. 新潟大学脳研究所腫瘍病態学分野、2. 新潟大学脳研究所分子神経生物学分野、3. 東京農業大学生物資源ゲノム解析センター、4. 東京大学大学院農学生命科学研究科、5. 東京農業大学生命科学部バイオサイエンス学科、6. 新潟大学脳研究所病理学分野、7. 福島県立医科大学医学部神経精神医学講座、8. 東北大学災害科学国際研究所災害精神医学分野、9. 新潟大学大学院医歯学総合研究科精神医学分野、10. 和歌山県立医科大学生体機能解析学研究室
*Yuriko Iwakura(1,2), Ryoka Kawahara-Miki(3), Satoshi Kida(4,5), Hidekazu Sotoyama(2), Ramil Gabdulkhaev(6), Hitoshi Takahashi(6), Yasuto Kunii(7,8), Mizuki Hino(7,8), Atsuko Nagaoka(7), Ryuta Izumi(7), Risa Shishido(7), Toshiyuki Someya(9), Hirooki Yabe(7), Akiyoshi Kakita(6), Hiroyuki Nawa(10,2)
Keyword: Epidermal growth factor, Schizophrenia, Early growth response 1, Auditory cortex
The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits such as prepulse inhibition, auditory steady-state response, and mismatch negativity in this model are relevant to those of schizophrenia. Using neurochemical approaches, we assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex. The increase in EGR1 levels in the model group were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this disorder and its animal models. | | 2022年7月2日 17:55～18:10 沖縄コンベンションセンター 会議場B3・4 第6会場
3O06e2-04
Cannabidiol modulates a schizophrenia-like bio-phenotype induced by repeated ketamine
*Charalampos Brakatselos(1), George Ntoulas(1), Michail Zois Asprogerakas(1), Olga Tsarna(1), Alexia Polissidis(2), Joana Silva(3), Ioannis Sotiropoulos(3), Joao Filipe Oliveira(3), Katerina Antoniou(1)
1. Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece, 2. Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 11527 Athens, Greece, 3. Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal ICVS/3B’s, PT Government Associate Laboratory, Braga, Portugal
Keyword: cannabidiol, ketamine, schizophrenia, rats
Ketamine (KET) has been used to generate schizophrenia-like behavioral features in rodents, while the neurobiological underpinnings are poorly understood. Cannabidiol (CBD) a non-addictive cannabis compound is reported to present antipsychotic properties, but the mechanisms involved are unknown. This study investigates the schizophrenia-like profile induced by repeated KET and explores the potential mitigating role of CBD using a variety of relevant experimental approaches. Sprague-Dawley rats have been treated with 30 mg/kg KET or saline for 10 days, and with 10 mg/kg of CBD, or vehicle for another 5 days. Two days after the last injection, rats underwent a battery of behavioral tests consisting of open-field activity, object recognition task, social interaction, pre-pulse inhibition, and amphetamine challenge. Moreover, dopaminergic and glutamatergic activity in specific brain regions were estimated with HPLC, while immunoblots determined the protein expression levels of neuroplasticity-related indices. Spine density and dendritic arborization analyses were performed in pyramidal cells from Golgi-cox-stained brains. Additionally, local field potentials have been recorded from anesthetized rat’s prefrontal cortex simultaneously with dorsomedial striatum and ventral hippocampus. KET-treated rats displayed impaired positive, negative, and cognitive symptomatology-related indices, only when KET treatment was not followed by CBD treatment. Neurochemical analyses have shown region-specific KET effects in dopamine biosynthesis that are counteracted by CBD while western blot analyses demonstrated an opposite modulation of NMDA receptor subunit composition in frontal and limbic areas, an effect that CBD partially mitigates. Synaptosomal expression of BDNF was affected in the hippocampus only by KET alone. The ongoing neurostructural and LFP analyses show prominent KET morphological and electrophysiological effects. KET induced a schizophrenia-related bio-phenotype in terms of behavior and the neurochemical and neurobiological analyses. CBD ameliorated or reversed the behavioral aspects of this schizophrenia-like model while affected KET-induced neurochemical alterations and modulated the neurobiological features region-specifically. The abovementioned findings characterize further the schizophrenia-like bio-phenotype induced by repeated KET, provide insights regarding schizophrenia pathophysiology, and enrich our understanding of the antipsychotic potential of CBD. | | 2022年7月2日 18:10～18:25 沖縄コンベンションセンター 会議場B3・4 第6会場
3O06e2-05
Behavioral and Molecular Characterization of a Novel Mouse Model of HERV-W Envelope Protein Expression
*Felisa Maria Herrero(1), Joel Gruchot(2), Hervé Perron(3,4), Patrick Küry(2), Ulrike Weber-Stadlbauer(1,5), Urs Meyer(1,5)
1. Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland, 2. Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany, 3. GeNeuro, 3, Chemin du pré Fleuri 1228 Plan-les-Ouates, Geneva, Switzerland, 4. Université de Lyon-UCBL, Lyon, France, 5. Neuroscience Center Zurich, Zurich, Switzerland
Keyword: Schizophrenia, Neurodevelopment disorder , Endogenous Retrovirus, Behavior
Human endogenous retroviruses (HERVs) are genetic elements derived from exogenous retroviral infections that took place throughout the evolution of the human genome. Increasing evidence implicates elevated expression of HERV type W envelope (HERV-W ENV) in psychotic disorders, including schizophrenia and bipolar disorder. To address this, we generated and characterised a novel mouse model that mimics transgenic expression of this HERV in mice.
Mice expressing HERV-W ENV were generated by inserting HERV-W ENV open reading frame (ORF) and the 3’ long terminal repeat (3’LTR) under the CAG promoter, into the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus. Adult transgenic (TG) mice and wild-type (WT) littermates were subjected to behavioral and cognitive phenotyping using a battery of tests assessing locomotor activity, innate anxiety-like behavior, social approach behavior and social recognition memory, sensorimotor gating, and novel object recognition. Next-generation RNA sequencing of hippocampal tissue was then used to identify genome-wide transcriptional changes in TG mice relative to WT controls. Ingenuity pathway analysis (IPA) was applied to explore molecular signaling pathways affected by HERV-W ENV expression.
TG mice with HERV-W ENV expression displayed a number of behavioral and cognitive anomalies, including increased locomotor activity in novel environments, impairments in social recognition memory and novel object recognition, as well as deficits in prepulse inhibition (PPI) of the acoustic startle reflex. Using a false discovery rate (FDR) threshold of 10% (q < 0.1), we found 199 genes deregulated in the hippocampus of TG mice relative to WT controls. Among those, several genes previously identified as genetic risk variants for schizophrenia and other psychotic disorders were found to be downregulated. Functional network prediction using IPA further demonstrated that the differentially expressed genes relate with functional nodes “neurodevelopmental disorders”, “schizophrenia”, “quantity of dendritic spines” and “synapse formation”.
Our preclinical data provide causal evidence for a role of HERV-W ENV expression in disrupting behavioral and cognitive functions implicated in schizophrenia. Moreover, our findings demonstrate that expression of this retroviral element has the capacity to change the brain transcriptome and cause a deregulated expression of genes associated with schizophrenia and other psychiatric disorders. | | | |
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