一般口演（Oral）

Oral Developmental Disorders: Animal Model 一般口演発達障害：モデル動物

7月27日（土）17:30～17:45　第8会場（朱鷺メッセ　3F　303+304） 3O-08e2-1 ナトリウムチャネル遺伝子SCN2A変異によるてんかん・知的障害・自閉症・統合失調症での興奮性神経伝達不全 Kazuhiro Yamakawa（山川和弘）^1,2,3，Hiroyuki Miyamoto（宮本浩行）^1,2，Tetsuya Tatsukawa（立川哲也）¹，Tetsushi Yamagata（山形哲司）¹，Matthieu Raveau（ラボマチュー）¹，Ikuo Ogiwara（荻原郁夫）^1,3 ¹理研CBS 神経遺伝 ²東京大国際高等研究所ニューロインテリジェンス国際研究機構 ³日本医科大医生理（システム生理） SCN2A gene encodes a voltage-gated sodium channel pore-forming alpha subunit Nav1.2. We found that, although at early-infantile stages Nav1.2 is predominantly expressed in inhibitory neurons in mouse brain, at later stages in neocortex and hippocampus Nav1.2 is mostly expressed in excitatory neurons but some in caudal ganglionic eminence (CGE)-derived inhibitory neurons. Expressions of Nav1.2 and Nav1.1 which is predominantly expressed in medial ganglionic eminence (MGE)-derived inhibitory neurons revealed to be mutually exclusive in most brain regions including neocortex, hippocampus, cerebellum, striatum and globus pallidus. SCN2A mutations recurrently appear in patients with epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ). Contrarily to the case of SCN1A in that missense and truncation mutations appear in milder and severer epilepsies (e.g., Dravet syndrome) respectively, SCN2A missense mutations appear in patients with severe epilepsies (e.g., early-infantile epileptic encephalopathy (Ohtahara syndrome), West syndrome and Lennox-Gastaut syndrome) while truncation mutations appear in those with ASD, ID or SCZ associating with later-onset milder epilepsies. Scn2a-haplodeficient (+/-) mice are therefore models for the latter cases. Scn2a (+/-) mice showed behavioral abnormalities, learning and memory impairments, abnormal hippocampal replay and increased gamma-activity. Impaired excitatory neurotransmission revealed to be responsible for some of critical disease phenotypes in the mice including absence-like epilepsy which suggested a novel neural circuit for epilepsy. References 1. Sugawara T, et al., Proc Natl Acad Sci USA 98: 6384-6389, 2001. 2. Kamiya K, et al., J Neurosci 24:2690-2698, 2004. 3. Ogiwara I, et al., Neurology 73: 1046-1053, 2009. 4. Yamagata T, et al., Biochem Biophyl Res Commun 491:1070-1076, 2017. 5. Ogiwara I, et al., Commun Biol 1, Article number: 96, 2018. 6. Middleton SJ, et al., Nat Neurosci 21:996-1003, 2018.		7月27日（土）17:45～18:00　第8会場（朱鷺メッセ　3F　303+304） 3O-08e2-2 15q11-13領域重複ASDモデルマウスの電気生理学的異常 Jin Nakatani（中谷仁）¹，Futoshi Toyoda（豊田太）²，Yasuhiro Go（郷康広）³，Shin-ichi Horike（堀家慎一）⁴，Natsu Koyama（小山なつ）⁵，Seiji Hitoshi（等誠司）⁵，Toru Takumi（内匠透）⁷，Ikuo Tooyama（遠山育夫）⁶，Shigehiro Morikawa（森川茂廣）⁶，Toshiro Inubushi（犬伏俊郎）⁶，Toshinori Sawano（澤野俊憲）¹，Hidekazu Tanaka（田中秀和）¹ ¹立命館大生命科学部薬理学 ²滋賀医科大学細胞機能生理学 ³自然科学研究機構生理学研究所 ⁴金沢大学学際科学実験センター ⁵滋賀医科大学統合臓器生理学 ⁶滋賀医科大学神経難病研究センター ⁷理研CBS Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder and the patients do not recover from their devastated states throughout life. Etiology of most cases with ASD remains unknown. We had already established model mice (Dp) that contain mouse chromosome 7 duplication, corresponding to human chromosome 15q11-13 duplication that is known as one of the most recurrent chromosomal abnormalities seen in patients with ASD. These mice showed impaired social interaction, behavioral inflexibility, anxiety, and so on. Many of these behaviors are considered to correspond to symptoms of ASD in human. Here we have generated homozygotes (DpDp) by crossing above heterogzygotes (Dp) . DpDp mice have two extra copies of 15q11-13, and it is expected that DpDp show more prominent biological features than heterozygote Dp. 80% of DpDp mice were lethal after birth. Magnetic resonance imaging (MRI) studies revealed DpDp have developmental abnormality in heart. The rest of 20% also showed developmental abnormalities including low body weight.DpDp mice showed developmental abnormalities including low body weight. Electrophysiological studies showed DpDp had severe cardiac rhythmic defects related with autonomic nerves system. This method was recorded by non-invasive way, so it can be applicable for the future diagnostic application in human ASD patients.

7月27日（土）18:00～18:15　第8会場（朱鷺メッセ　3F　303+304） 3O-08e2-3 NAD+前駆体摂取によるCD157ノックアウトマウスの社会性行動障害と不安行動の改善効果検証 Maria Gerasimenko（ゲラシメヌコマリア）^1,2，Stanislav Cherepanov（ちぇれぱのふすたにすらぶ）²，Shigeru Yokoyama（横山茂）²，Haruhiro Higashida（東田陽博）² ¹大阪大学・金沢大学・浜松医科大学・千葉大学・福井大学　連合小児発達学研究科 ²子どものこころの発達研究センター A lot of studies revealed positive effects of NAD + precursors' supplementation on the physical condition in a case of neurodegenerative disorders First of all mitochondria activity and biogenesis, with muscular dystrophy, and senescence. NAD + levels have beneficial effects on brain function, especially on social memory and interaction. NAD + busting can pot potentially have an effect in different ways. Second metabolism elevation. Second NAD + elevation can lead to mTOR inhibition via sirtuins pathway. c ADPR, as a Ca 2 + mobilizing second messenger, c ADP-ribose (cADPR)is shown to be a critical molecule in social behavior by releasing oxytocin from the hypothalamus into the brain.In our study we focused on the effect of CD 157 KO mouse model for autism spectrum disorder, which displays anxiety, depression and social impairment from the side of oxytocin release pathways. CD 157 KO and C 57 BL 6 mice were treated with an NAD + precursor at the dose of 3 or 13 mg / mouse / day in PBS solution or placebo in equal volume through gavage. The procedure of gavage was performed daily in the same time period for 12 days. On 13th day behavioral experiments: three-chamber and light-dark Social behaviors in the three-chamber or dark-light transition tests are improved after daily gavage for 12 days in CD 157 knockout mice,Cerebrospinal fluid oxytocin levels and NAD + levels were increased after gavage application in CD 157 knockout mice, but of saline. Elevation of oxytocin level did not accompany by ADPR cyclase activity. The results demonstrate for the first time that the NAD + precursor supplementation has beneficial effects on social impairment in rodents and suggest a possible treatment for social defects in human psychiatry disorders in the future.The results demonstrate for the first time that the NAD + precursor supplementation has beneficial effects on social impairment in rodents and suggest a possible treatment for social defects in human psychiatry disorders in the future.The results demonstrate for the first time that the NAD + precursor supplementation has beneficial effects on social impairment in rodents and suggest a possible treatment for social defects in human psychiatry disorders in the future.		7月27日（土）18:15～18:30　第8会場（朱鷺メッセ　3F　303+304） 3O-08e2-4 銀ナノ粒子による多動性障害ラットに見られるCNV Masami Ishido（石堂正美）国環研・健康リスク評価 For long time, we had believed that the fetus would be guaranteed by a placenta against foreign materials until thalidomide and diethylstilbestrol (DES) had been found to exert harmful effects on the fetus. After then, reproductive and developmental testing for chemicals is legally carried out with obligation. However, recent research shows evidence that some chemical effects were inherited through the next generation: even that is a single exposure. Standing on this fact, we examined if hyperactivity seen in ADHD or autism would be inherited in the rat. We exposed pregnant rat (E7 day) to silver nanoparticle (4mg/kg), after which we never exposed it, again. Then, we got hyperactive rats at next generation by outcross. Also, at F3 generation, we got hyperactive rats by mating with female control rats. We developed two lines of the model. They were 1.4~1.5 fold higher than that of control in the spontaneous motor activity. They were not soft inheritance. Possible etiology of autism might come from genetic factors and/or maternal life style in pregnancy. Particularly, much attention has been paid to copy number variants (CNVs) in patients with autism. There are many CNVs reported, in particular, 16p11.2 has much attention, because it was reported in many psychological disorders, not only autism but also ADHD, schizophrenia, and bipolar disorders. Therefore, we examined CNV in our hyperactive rats. There were many CNVs found, including chromosomes 1 to 20, except chromosomes 5, 7 12 19. Both amplification and/or deletion occur. Intense fluoresce signals were found in chromosomes 1,2 3,6, and 20. We are now examining if these CNVs is pathogenic or not.