一般口演
てんかん / うつ病と双極性障害
Epilepsy / Depression and Bipolar Disorders
座長：山川 和弘（名古屋市立大学 大学院医学研究科） |
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| 2022年7月2日 15:00～15:15 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04a2-01
ナトリウムチャネルNav1.1の大脳皮質５層錐体路投射細胞における発現はドラべ症候群における突然死神経回路を明らかにする
Expression of sodium channel Nav1.1 at neocortical layer V pyramidal tract neurons elucidates a neural circuit for sudden death in Dravet syndrome
*山川 和弘(1)、鈴木 俊光(1)、山形 哲司(1)
1. 名古屋市立大学
*Kazuhiro Yamakawa(1), Toshimitsu Suzuki(1), Tetsushi Yamagata(1)
1. Nagoya City University
Keyword: epilepsy, SCN1A, Nav1.1, Dravet syndrome
Voltage-gated sodium channels consist of one main pore-forming alpha- and one or two subsidiary beta-subunits that regulate kinetics or subcellular trafficking of the alphas. Human has nine alphas (Nav1.1~Nav1.9) and four betas (beta-1~beta-4). Nav1.1 is encoded by SCN1A gene, and de novo loss-of-function mutations of SCN1A are found in more than 80% of the patients with Dravet syndrome characterized by a sporadic intractable epileptic encephalopathy characterized by early onset (6 months ~ 1 year after birth) epileptic seizures which firstly appear as febrile but later could be afebrile, intellectual disability, autistic features, ataxia and increased risk of sudden unexpected death in epilepsy (SUDEP). Mutations of SCN2A encoding Nav1.2 are also well described in patients with autism intellectual disability and epilepsy. Expressions of Nav1.1 and Nav1.2 are mutually exclusive in most brain regions. In adult neocortex, Nav1.1 is dominant in parvalbumin-positive inhibitory neurons (PV-IN) while Nav1.2 is dominant in excitatory neurons. Although a distinct subpopulation of neocortical excitatory neurons was also reported to express Nav1.1, their nature has been uncharacterized. By using newly-generated transgenic mouse lines expressing Scn1a promoter-driven green fluorescent protein (GFP), here we confirm mutually-exclusive expressions of Nav1.1 and Nav1.2, absence of Nav1.1 in hippocampal excitatory neurons, and further show that among neocortical excitatory neurons Nav1.1 is expressed in pyramidal tract (PT) and a subpopulation of cortico-cortical while Nav1.2 in cortico-striatal, cortico-thalamic and a distinct subpopulation of cortico-cortical projection neurons. Because parasympathetic hyperactivity is assumed to be a basis for cardiac arrest and SUDEP in Dravet syndrome and Nav1.1 haploinsufficiency in neocortical excitatory excitatory neurons is ameliorating for SUDEP in Dravet syndrome, the pathological neural circuit was assumed to be as follows, "Nav1.1 haploinsufficiency in neocortical PV-IN fails to suppress and therefore activates PT neurons as well as subsequent parasympathetic neurons and consequently suppresses heart activity and results in cardiac arrest". | | 2022年7月2日 15:15～15:30 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04a2-02
てんかん発作時波形にみられるデータ駆動的に抽出された新規の特徴
A new data-driven electrophysiological feature to detect epileptic seizures
*山本 祥太(1,2)、栁澤 琢史(2,1)、福間 良平(1,2)、押野 悟(1)、谷 直樹(1)、Hui Ming Khoo(1)、枝川 光太朗(3)、小林 真紀(4)、田中 將貴(1,2)、藤田 祐也(1,2)、貴島 晴彦(1)
1. 大阪大学大学院医学系研究科脳神経外科学、2. 大阪大学高等共創研究院、3. 大阪急性期総合医療センター脳神経外科、4. 関西労災病院脳神経外科
*Shota Yamamoto(1,2), Takufumi Yanagisawa(2,1), Ryohei Fukuma(1,2), Satoru Oshino(1), Naoki Tani(1), Hui Ming Khoo(1), Kohtaro Edagawa(3), Maki Kobayashi(4), Masataka Tanaka(1,2), Yuya Fujita(1,2), Haruhiko Kishima(1)
1. Dept of Neurosurgery, Graduate School of Medicine, Osaka University, Osaka, Japan, 2. Institute for Advanced Co-Creation Studies, Osaka University, Osaka, Japan, 3. Dept of Neurosurgery, Osaka General Medical Center, Osaka, Japan, 4. Dept of Neurosurgery, Kansai Rosai Hospital, Hyogo, Japan
Keyword: data-driven epileptogenicity index, epilepsy, deep learning, integrated gradients
Objectives Some spectral features of intracranial electroencephalogram (iEEG) signal have reported to be useful in seizure detection or seizure onset zone localization. Moreover, some of them have led to the understanding of physiological mechanism of the seizure. Recently, deep learning has been reportedly useful in classifying electrophysiological signal but, the spectral features detected by it have not been revealed. Our aim of this research is to identify a new electrophysiological feature common across different types of epilepsy, using deep learning and a method modified from the integrated gradient method which measures the contribution of input features to classification. Methods One hundred and nine seizures were recorded from 21 patients with multiple types of refractory epilepsy. The raw iEEG signal of the early phase of epileptic seizures and interictal states were classified by a one-dimensional convolutional neural network named Epi-Net. For comparison, the same signals were classified by a support vector machine (SVM) using a spectral power of 8 frequency bands (δ, θ, α, β, low,high-γ, HFO, and 250–500 Hz) and phase amplitude coupling between the γ amplitude and the α or β phase. Then a modified integrated gradients method was used for revealing the feature learned by Epi-Net. We considered the product of powers multiplied by the relative contribution of each frequency amplitude as a data-driven epileptogenicity index (d-EI). Then the d-EI was compared to other conventional features in terms of accuracy to detect epileptic seizures. Finally, we compared the d-EI among the electrodes to evaluate its relationship with the resected area and the Engel classification. Results Epi-Net outperformed the SVM, with an area under the receiver operating characteristic curve of 0.944 ± 0.067, which was significantly larger than that of the SVM (0.808 ± 0.253; p = 0.025). The learned iEEG features were characterised by increased powers of 17–92 Hz and >180 Hz and decreased powers of other frequencies. The d-EI detected the epileptic seizures with better accuracy than other iEEG features. Moreover, the surgical resection of areas with a larger increase at seizure onset in d-EI was significantly associated with seizure outcomes. Discussions We revealed a new iEEG feature d-EI from the trained Epi-Net. The revealed contribution of each frequency component to detecting epileptic seizures may lead to the understanding of new physiological mechanisms of the seizure. | | 2022年7月2日 15:30～15:45 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04a2-03
[(11)C]K-2を用いたうつ病モデル動物の層別化と新規治療戦略
Stratification of animal models of depression using [(11)C]K-2 and development of novel therapeutic strategy of depression
*中島 和希(1)、宮崎 智之(1)、有澤 哲(1)、波多野 真依(1)、高橋 琢哉(1)
1. 横浜市立大学医学研究科生理学
*Waki Nakajima Nakajima(1), Tomoyuki Miyazaki(1), Tetsu Arisawa(1), Mai Hatano(1), Takuya Takahashi(1)
1. Dept Physilogy, Grad Sch Med, Yokohama City Univ, Japan
Keyword: AMPA receptor, depression, Positive allosteric modulators, [11C]K2
AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor is one of the most important molecules controlling the neuronal activities. Dysfunction of AMPA receptors is believed to underlie some of psychiatric disorders. Recent studies have clarified that AMPA receptors expression is decreased in post-mortem brain of patients with major depressive disorder (Gibbons et al., 2012, Duric et al., 2013). PAMs (Positive allosteric modulators) enhancing AMPA receptors function have been developed toward patients with depression but the effects of PAMs on depression seem to be limited (Machado-Vieira et al., 2017). This reason is inadequate stratification of responder or non-responder for PAMs. Here we show that three rodent depression models are stratified using [11C]K-2, PET tracer for AMPA receptors, and a new type of PAMs targeting AMPA receptors improves the rodent depression model with decreased AMPA receptor expression. We scanned WKY (Wistar Kyoto) rats, aLH (acute learned helplessness) rats and OBX (Olfactory bulbectomy) rats. aLH rats and OBX rats didn’t change AMPA receptor expression, but WKY rats showed decreased AMPA receptor levels in mPFC (medial prefrontal cortex) and BLA (basolateral amygdala). Since [11C]K2 has previously shown to recognizes the membrane surface of AMPA receptors (Arisawa et al., 2021), AMPA receptor levels on the cell membranes were decreased in WKY rats. We synthesized a novel compound, K-4, hydrolysis-resistant form of K-2. Electrophysiological experiments revealed that this compound increased AMPA receptors current in the CA3-CA1 synapses. To elucidate whether a new compound is effective on improving depressive phenotype of rodent depression model, we performed FST (forced swim test) to examine anti-depressive effect of K4 in aLH rats, OBX rats and WKY rats. Interestingly, K-4 reduced immobility time in WKY rats but not in aLH rats and OBX rats, indicating that K-4 has antidepressant effects in a depression model with low AMPA receptor levels. Taken together, [11C]K2 PET images can stratify the depression models, and K-4 has only antidepressant effect in WKY rats. We can propose a novel therapeutic strategy which observe and treat the depression models. | | 2022年7月2日 15:45～16:00 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04a2-04
腹側内側中脳橋のGABA作動性神経が睡眠恒常性と睡眠構築の変化を伴う躁様行動に関与する
GABAergic neurons in Ventral Midbrain/Pons are involved in mania-like behaviors with altered sleep homeostasis and sleep architecture
*本多 隆利(1,2)、高田 陽子(2)、Yoan Cherasse(2)、水野 聖哉(3)、杉山 文博(3)、高橋 智(2,3)、船戸 弘正(2,4)、柳沢 正史(2,5,6,7)、Michael Lazarus(2)、大石 陽(2)
1. マサチューセッツ工科大学（MIT）Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences、2. 筑波大学国際統合睡眠医科学研究機構（WPI-IIIS）、3. 筑波大学トランスボーダー医学研究センター／筑波大学生命科学動物資源センター、4. 東邦大学医学部解剖学講座、5. テキサス大学サウスウェスタン（UTSW）メディカルセンター Department of Molecular Genetics、6. 筑波大学生存ダイナミクス研究センター、7. 筑波大学未来社会工学開発研究センター
*Takato Honda(1,2), Yohko Takata(2), Yoan Cherasse(2), Seiya Mizuno(3), Fumihiro Sugiyama(3), Satoru Takahashi(2,3), Hiromasa Funato(2,4), Masashi Yanagisawa(2,5,6,7), Michael Lazarus(2), Yo Oishi(2)
1. Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology (MIT), Cambridge, USA, 2. International Institute for Integrative Sleep Medicine (WPI-IIIS), Univ of Tsukuba, Tsukuba, Japan, 3. Laboratory Animal Resource Center and Trans-border Medical Research Center, Univ of Tsukuba, Tsukuba, Japan, 4. Department of Anatomy, Faculty of Medicine, Toho University, Tokyo, Japan, 5. Department of Molecular Genetics, University of Texas Southwestern (UTSW) Medical Center, Dallas, USA, 6. Life Science Center for Survival Dynamics (TARA), Univ of Tsukuba, Tsukuba, Japan, 7. R&D Center for Frontiers of Mirai in Policy and Technology (F-MIRAI), Univ of Tsukuba, Tsukuba, Japan
Keyword: Bipolar Disorder, Mania, Sleep, Sleep Homeostasis
In sleep biology, neural mechanisms of sleep homeostasis, which is known as the existence of rebound sleep after sleep deprivation, remain as a core unrevealed question. In sleep medicine, sleep problems are highly associated with neuropsychiatric disorders such as bipolar disorder characterized by periods of depression and mania. Patients with mania persistently exhibit hyperactivity, elevated mood, and decreased need for sleep. However, brain areas and neuronal populations involved in mania remain elusive. In this study, we selectively ablated GABAergic neurons in ventral medial midbrain/pons (VMP) by Cre-dependent viral expression of diphtheria toxin subunit A (AAV-FLEX-DTA) in VMP of VGAT-Cre mice (VGAT-CreDTA/VMP). For controls, we prepared the mice expressing humanized Renilla reniformis-derived GFP (AAV-FLEX-hrGFP) in VMP GABAergic neurons (VGAT-CrehrGFP/VMP). For these mice, we performed comprehensive behavioral test battery and electroencephalography (EEG)/electromyography (EMG)-based sleep/wake analysis. To investigate the involvement of the dopamine system, we newly generated D2 receptors knockout mice in VGAT-Cre background by CRISPR/Cas9 system (VGAT-Cre;D2R-/-). We found that ablation of VMP GABAergic neurons induced mania-like behaviors in mice, including hyperactivity, anti-depressive behaviors, reduced anxiety, increased risk-taking behaviors, distractibility, and an extremely shortened sleep time. Strikingly, these mice also exhibited no rebound sleep after sleep deprivation, suggesting abnormal sleep homeostatic regulation. Furthermore, dopamine D2 receptor deficiency largely abolished the sleep reduction induced by ablating the VMP GABAergic neurons without affecting the hyperactivity and anti-depressive behaviors. In summary, our data demonstrate that VMP GABAergic neurons are involved in the expression of mania-like behaviors, which can be segregated to the short-sleep and other phenotypes on the basis of the dopamine D2 receptors. In this conference, we also discuss our recent pharmacological studies using VGAT-CreDTA/VMP mice. | |
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