一般口演（Oral）

Oral Neurodevelopmental Disorders 一般口演神経発達障害

7月26日（金）16:10～16:25　第8会場（朱鷺メッセ　3F　303+304） 2O-08a2-1 Short term estradiol treatment reduces seizure severity but does not improve cognitive measures in mouse models of congenital epilepsy and intellectual disability. Karagh Eleni Loring（Loring Karagh Eleni）¹，Kristie Lee（Lee Kristie）^1,2，Tessa Mattiske（Mattiske Tessa）^1,2，Aneta Zysk（Zysk Aneta）^1,2，Matilda R Jackson（Jackson Matilda R）^1,2，Cheryl Shoubridge（Shoubridge Cheryl）^1,2 ¹The University of Adelaide ²Robinson Research Institute Children with severe intellectual disability have an increased prevalence of seizures, estimated at 15-20% higher than the general population and typically have poor responses to anti-convulsant medication. Neurosteroid treatment may improve seizure outcomes, but the mechanisms remain unknown. Here we investigate seizure and cognitive phenotypes in mice following short term, daily delivery of the neurosteroid 17β-estradiol (40 ng/g) in early postnatal life. The mice model mutations in the Aristaless-related homeobox gene (Arx) expanding the first (PA1) or second (PA2) polyalanine tract, invariably causing intellectual disability, with frequent severe and refractory infantile seizures. In a blinded study, we showed that 17β-estradiol treatment significantly reduced the number and severity of seizures in both mouse strains compared to vehicle treated mutant mice. The frequency of observed seizures on daily handling (n = 14 mice/treatment/genotype) were significantly reduced in PA1 treated mice (34% reduction), providing reproducible outcomes of an alternate PA1 model. Expanding the analysis to the PA2 mice demonstrates a 15% reduction in seizure frequency with treatment. Spontaneous seizure activity was recorded through non-invasive video monitoring at 7 weeks of age (n = 7 mice/treatment/genotype) coinciding with peak seizure activity. Using a scale based on the International League Against Epilepsy's classification system we show that PA1 treated mice no longer present with the most severe category of prolonged myoclonic seizures. Even more striking, PA2 treated mice had a complete absence of any seizures during this analysis. Behavioural tests were performed on mice before and after peak seizure onset. Despite the reduction in seizure occurrence and severity, 17β-estradiol treated mice showed no improvement in cognitive outcomes at post peak seizure onset (two months of age). For the first time, we show that cognitive deficits due to mutations in Arx are already present prior to seizure onset and do not worsen with seizures. ARX is a transcription factor and Arx PA mutant mice have de-regulated transcriptome profiles in the developing embryonic brain. We contend that 17β-estradiol administration in early postnatal life improves seizure outcomes due to changes in gene expression pathways that are distinct to the deregulated gene pathways involved in manifesting cognitive deficits.		7月26日（金）16:25～16:40　第8会場（朱鷺メッセ　3F　303+304） 2O-08a2-2 Maternal immune activation adversely affects the offspring microglia via Type-I interferon signaling Hila Ben-Yehuda（Ben-Yehuda Hila）^1,2，Orit Matcovitch-Natan（Matcovitch-Natan Orit）^1,2，Aleksander Kertser（Kertser Aleksander）¹，Amit Spinrad（Spinrad Amit）^1,2，Ido Amit（Amit Ido）²，Michal Schwartz（Schwartz Michal）¹ ¹Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. ²Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. Neurodevelopmental diseases are often associated with viral infection during pregnancy. In mice, Maternal Immune Activation (MIA) results in cognitive and social abnormalities of the offspring at adulthood. However, the underlying mechanism is still not fully understood. Here we hypothesized that prenatal immune challenge might impact the developing microglia in a type-I interferon-dependent manner. To test this hypothesis, we treated pregnant dams with the viral mimetic poly(I:C), a TLR3 ligand, as the prenatal inflammatory stimuli, 14.5 days following gestation, and compared the microglia isolated from their offspring to microglia isolated from offspring of PBS treated pregnant controls. Using high-throughput mRNA sequencing and gene ontology analyses, we found a reduction in expression of genes related to proliferation and cell cycle in the microglia isolated from newborn offspring of poly(I:C) injected dams. The reduction of proliferation was confirmed by flow cytometry analysis, assessing microglial expression of the proliferation marker Ki67. Moreover, RTqPCR examination of embryonic yolk sac, the origin of microglia in the developing offspring, following the maternal poly(I:C) treatment, showed a signature of genes related to type-I interferon, compared to control samples. Blocking maternal interferon type-I signaling by systemic administration of antibody directed against interferon receptor-1, one day prior to the MIA, prevented some of the effect of MIA on the newborn microglia. Furthermore, systemic treatment of pregnant dams with IFNβ, led to a reduction in expression of Ki67 relative to control samples, which recapitulates to some extent the MIA. Moreover, maternal separation of IFNβ pups, led to a higher activation of their microglia, as compared to controls. Our results suggest that immune activation during pregnancy upregulates maternal interferon type-I that in turn interferes with the microglia programmed development cascade, which could impact neurodevelopmental conditions at adulthood.

7月26日（金）16:40～16:55　第8会場（朱鷺メッセ　3F　303+304） 2O-08a2-3 精神疾患関連エピジェネティクス因子の欠損が、マウス内側前頭前野錐体細胞への興奮性シナプス入力の減弱と異常行動を引き起こす Kenichiro Nagahama（長濱健一郎）^1,2，Kazuto Sakoori（佐郡和人）^1,2，Takaki Watanabe（渡邉貴樹）^1,2，Michinori Koebis（古戎道典）³，Naofumi Uesaka（上阪直史）^1,2，Atsu Aiba（饗場篤）³，Masanobu Kano（狩野方伸）^1,2 ¹東京大学大学院医学系研究科機能生物学専攻神経生理学分野 ²東京大学国際高等研究所ニューロインテリジェンス研究機構 ³東京大学大学院医学系研究科疾患生命工学センター動物資源研究領域 Clinical studies on patients with psychiatric disorders indicate that several epigenetic factors are potential regulators of candidate genes related to schizophrenia and autism spectrum disorders. However, it remains unclear how abnormalities in epigenetic factors affect normal brain function and causes psychiatric disorder-like behavioral phenotypes. In recent reports, de novo loss-of-function (LoF) variants that encode some epigenetic factors were identified in a small population of psychiatric patients, suggesting that these genes may play an important role in the onset of the psychiatric disorders. In the present study, to tackle how one of the epigenetic factors is related to pathophysiology of the psychiatric disorder, we examined roles of the factor in synaptic function in mice. We generated the knockout (KO) mice carrying the mutation similar to the patients with LoF variants of the epigenetic factor by CRISPR-Cas9 system. We prepared coronal brain slices from the mice at postnatal days 16-25 and performed whole-cell recording from layer 2/3 (L2/3) pyramidal neurons in the medial prefrontal cortex (mPFC). We recorded excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) and compared them between the KO and wild-type mice. We found impaired excitatory synaptic transmission on pyramidal neurons. In addition, we also performed RNA interference-mediated knockdown (KD) of the factor specifically in L2/3 pyramidal neurons of the mPFC by in utero electroporation at embryonic day 14. We confirmed that EPSCs were significantly reduced pyramidal cells with the KD compared with control cells in the same slices. Finally, we performed behavioral analyses using the KO and the frontal cortex-specific KD mice of the epigenetic factor. These mice exhibited several behavioral abnormalities relevant to the clinical symptoms of the psychiatric disorder. Overall, our results suggest that the epigenetic factor is involved in the development and/or maintenance of excitatory synaptic transmission in L2/3 pyramidal neurons of the mPFC and defect of this factor causes reduced excitatory synaptic transmission and psychiatric disorder-like abnormal behavior in mice.		7月26日（金）16:55～17:10　第8会場（朱鷺メッセ　3F　303+304） 2O-08a2-4 ミエリン脂質代謝異常が惹起する先天性脳白質障害の病態解析及び治療法開発へのアプローチ Yasushi Enokido（榎戸靖）¹，Shinji Go（郷慎司）²，Soichiro Kishi（岸宗一郎）¹，Hiroshi Takase（高瀬弘嗣）³，Kiyofumi Asai（浅井清文）³，Hirohide Takebayashi（竹林浩秀）⁴，Junko Matsuda（松田純子）² ¹愛知県心身障害者コロニー発達障害研究所 ²川崎医科大・医 ³名古屋市大院・医 ⁴新潟大院・医歯学 Myelin is a sheath-like structure wrapping around the nerve axon. It is formed by electrically insulating membranes that allows to propagate saltatory conduction of nerve impulse. Impaired myelination in the developing brain is thought to link to neurodevelopmental disorder, such as autism spectrum disorder. In the brain, the most abundant myelin lipids are cholesterol and galactosylceramide (galactocerebroside), and the dysregulations of each lipid metabolism associate with Niemann-Pick disease type C (NPC) and Krabbe disease (KD), lysosomal storage diseases with inherited leukodystrophy that caused by mutations in the genes of NPC1 and GALC, respectively. The majority of each disease patients exhibit characteristic psycho-motor and/or intellectual disabilities during development; however the underlying pathophysiology remain largely unknown, and effective treatments have yet to be established. We previously reported that oligodendrocytes (OL) isolated from NPC and KD model mice exhibit developmental defects and impaired myelination. In addition, we found that activation of Akt/mTOR signaling pathway, a critical regulator for OL differentiation and myelination, is significantly reduced in differentiating KD OLs (Inamura et al., Neurobiol Dis 2018). Here, to gain a new insight into the therapeutic strategy for NPC and KD, we investigated the pathological and therapeutic role of Akt/mTOR signaling pathway and several microRNAs in differentiating OLs derived from NPC and KD mouse brains.