Poster

Poster 22 ADHD/ASD/Epilepsy 2 ポスター 22 ADHD/ASD/てんかん2

P22-1 Analysis of macrophage in autism spectrum disorder 自閉スペクトラム症におけるマクロファージ解析 Yamauchi Takahira（山内崇平），牧之段学，奥村和生，鳥塚通弘，萱嶋善徳，小森崇史，岸本年史 Department of Psychiatry, Nara Medical University School of Medicine, Kashihara, Japan 自閉スペクトラム症（Autism Spectrum Disorder : ASD）は、現在有病率が1～2%と以前に比べて高い頻度を示し、専門医療機関への受診も増加しており、社会的な関心が高い疾患である。多くの研究が行われているが、その病因及び病態は解明されていない。遺伝学研究では、遺伝要因が大きいことは周知されているが、それに加えて環境要因の重要性についても報告されている（Hallmayer et al., Arch Gen Psychiatry 2011）。母体の免疫活性に暴露した胎児がASDの表現型を呈すると、疫学研究やモデルマウス研究で報告されている。死後脳研究では、慢性の神経炎症所見や免疫、ミクログリア関連遺伝子の過剰発現が報告されており、臨床的にもPETを用いた研究で、ASD患者でミクログリアが活性化していることが報告されている。これらのことから、ASDは遺伝要因だけではなく、環境要因またそれらによる炎症、免疫機構の関与が想定されている。ASDはアレルギー疾患の併存が多いと報告されており、メタ解析において、ASDは気管支ぜん息及びアレルギー性鼻炎の有病率が有意に高いと報告されており（Miyazaki et al., Rev J Dev Disord 2015）、中枢神経系だけではなく末梢組織においても免疫応答の亢進が想定される。自然免疫やアレルギー応答においてマクロファージが重要な役割を担っており、機能的にM1型とM2型に分別され、M1型は細菌・ウイルス感染に対して炎症性サイトカインの発現を増強させ、M2型はIL-10やTGF-βなどの発現を介して抗炎症性作用をもたらす。我々はASD患者の血液から末梢血単核球を分離し、磁性分離法にて単球を単離した。その後、サイトカイン（GM-CSF、M-CSF）の存在下で培養し、それぞれM1マクロファージまたはM2マクロファージへ分化させ、RT-PCR法にてサイトカイン（IL-1b, IL-6, TNF-a）について検討した。その結果、ASD患者群でM1マクロファージにおけるTNF-a遺伝子発現量とASD特性を測定する自己評定尺度（AQ-J）の合計点および下位尺度の想像力が有意に相関していた。これらから、マクロファージがASDの病態生理に関与している可能性が示唆された。		P22-2 Decision making under sunk costs in autism spectrum disorder 自閉スペクトラム症における埋没費用効果に関する研究 Fujino Junya（藤野純也）^1,2，鄭志誠^1,2,3,4，板橋貴史¹，青木悠太¹，太田晴久^1,5，金井智恵子¹，久保田学^1,6，橋本龍一郎^1,7，中村元昭^1,8，加藤進昌¹，高橋英彦^1,2 ¹Medical Institute of Developmental Disabilities Research, Showa University, Tokyo, Japan ²Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan ³Institute of Applied Brain Sciences, Waseda University, Saitama, Japan ⁴School of Human and Social Sciences, Tokyo International University, Saitama, Japan ⁵Department of Psychiatry, School of Medicine, Showa University, Tokyo, Japan ⁶National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan ⁷Department of Language Sciences, Graduate School of Humanities, Tokyo Metrop olitan University, Tokyo, Japan ⁸Kanagawa Psychiatric Center, Kanagawa, Japan The sunk cost effect is the tendency to continue an investment or take an action even though it has higher future costs than benefits, if costs of time, money, or effort were previously incurred. This decision bias is pervasive in real life and has been studied in various disciplines, including psychology, economics, politics, organizational behavior, and biology. Previous studies suggest that individuals with autism spectrum disorder (ASD) have reduced sensitivity to context stimuli and make more rational and consistent choices in various types of experimental situations. However, it remains unclear whether this also applies to decision-making in the context of the sunk cost effect. To address this issue, we modified a task that clearly shows the sunk cost effect and used it to evaluate this behavior in individuals with ASD. We found that the sunk cost effect was reduced in the ASD group compared with the control group. Furthermore, unlike in the control participants, the sunk cost effect was not increased when larger sunk costs were incurred in individuals with ASD. Choice reaction time was also less influenced by sunk costs in ASD participants than in control participants. The current results extend previous findings by showing that the reduced context sensitivity that characterizes ASD spills over into the context of the sunk cost effect. Our findings will contribute to a better understanding of altered decision-making in individuals with ASD and may be useful in addressing the practical implications of their socioeconomic behavior.

P22-3 Identification of PHACTR1 as a novel causal gene for West Syndrome and pathophysiological significance of the gene mutations West syndromeの新規原因遺伝子Phactr1のde novo遺伝子変異の同定と病態学的解析 Hamada Nanako（浜田奈々子）^1,2，大萱俊介³，中島光子⁴，西條琢磨⁵，才津浩智⁴，加藤光広⁶，松本直通⁴，籾山俊彦⁵，永田浩一¹ ¹Dept. of Mol. Neurobiol., Inst. for Developmental Res., Aichi Human Service Center ²Res. Fellow of Japan Society for the Promotion of Sci. ³Central Hospital, Aichi Human Service Center ⁴Dept. of Human Genetics, Yokohama City Univ. Graduate School of Med. ⁵Dept. of Pharmacology, Jikei Univ. School of Med. ⁶Dept. of Pediatrics, Showa Univ. School of Med. Trio-based whole exome sequencing identified 2 de novo heterozygous missense mutations (c.1449T>C; p.Leu500Pro and c.1436A>T; p.Asn479Ile) in PHACTR1, encoding a molecule critical for the regulation of protein phosphatase 1 (PP1) and actin cytoskeleton, in unrelated Japanese individuals with West syndrome (infantile spasms with intellectual disability (ID)). We then examined the role of Phactr1 in the development of mouse cerebral cortex and pathophysiological significance of these 2 mutations and another (c.1561C>T, p.Arg521Cys), which had been reported in an undiagnosed ID patient. Immunoprecipitation analyses revealed that actin-binding activity of PHACTR1 was impaired by the p.Leu500Pro and p.Asn479Ile mutations while the p.Arg521Cys mutant exhibited reduced binding to PP1. Acute knockdown of Phactr1 with in utero electroporation caused defects in cortical neuron migration and dendritic arbor formation during corticogenesis. Notably, these phenotypes were rescued by an RNAi-resistant PHACTR1, but not by the mutants. Forced expression of the mutants per se also exhibited aberrant phenotypes in neuronal migration. These results suggest gain-of-function of the mutant allele. Electrophysiological analyses revealed abnormal synaptic properties in Phactr1-deficient excitatory cortical neurons. Taken together, PHACTR1 abnormalities were found to cause West syndrome probably due to morphological and functional defects in cortical neurons during brain development.		P22-4 Brain glycogen is involved in the increase of brain lactate level after electroconvulsive seizure 電気けいれん後の脳内乳酸増加には脳内グリコーゲンが関与している Kanamatsu Tomoyuki（金松知幸）¹，先崎由樹²，迫川弘一² ¹Department of Science and Engineering for Sustainable innovation, Soka University, Tokyo, Japan ²Department of Environmental Engineering for Symbiosis, Faculty of Engineering, Soka University, Tokyo, Japan The purpose of this study is to examine the metabolism of glycogen in the brain and to know the possibility that the brain lactate is synthesized from brain glycogen during the convulsion. After 24-hour fasting, the rats were given [1-¹³C]-glucose solution (10%) for 6 hours as drinking water and then replaced with non-labeled glucose solution (10%) for additional 2.5 hours. Then the rats were treated with electroconvulsive shock (ECS) with 36 mA for 0.5 sec under slight anesthesia, and then were exposed to microwave (4.8 kw for 2.1 sec) 6 minutes after ECS treatment. The brains were dissected into two regions (frontal cortex and hippocampus). The contents of glucose, lactate and glycogen in each brain region were measured with the assay kits. The ¹³C fractional enrichment (¹³C-FE) of glucose, lactate and glycogen were measured by ¹³C- and ¹H- nuclear magnetic resonance (NMR) spectroscopy. ECS induced the increase of brain lactate levels and the decrease of brain glycogen levels, however, no change in the brain glucose levels. The ¹³C- and ¹H-NMR studies demonstrated that the ¹³C-FE of brain glucose was lower than that of brain lactate and glycogen before ECS treatment. After ECS treatment, the ¹³C-FE of brain lactate was increased and that of brain glycogen was decreased, however that of brain glucose did not changed. These results might indicate that the substrate for synthesizing lactate during the convulsive seizure is brain glycogen but not brain glucose.

P22-5 Involvement of OCTN1 in pentylenetetrazole-induced seizure in rodents 膜輸送体OCTN1/SLC22A4のpentylentetrazole誘発けいれん発作に及ぼす役割 Komori Tomoe（小森友恵），中道範隆，西山美沙，増尾友佑，加藤将夫 Fac. Pharm., Kanazawa Univ., Kanazawa, Japan [Purpose] OCTN1 is functionally expressed in neurons and neural stem cells. The aim of the present study was to clarify pathophysiological role of OCTN1 in the central nervous system as a possible target for epilepsy treatment.[Methods] Pentylenetetrazole (PTZ)-induced seizures were caused by repeated intraperitoneal administration in both wild-type and gene-knockout (octn1-/-) mice as a model of epilepsy. Severity of seizure was evaluated by a score of 5 stages.[Results and Discussion] As the number of dose increased, the seizure score worsened in wild-type, but that in octn1-/- was not so much. PTZ administration significantly increased expression of seizure-associated genes such as c-fos, Arc, and Egr1 in wild-type hippocampus, whereas gene expression of only Egr1, but not c-fos or Arc, was significantly increased in octn1-/-, suggesting that octn1 gene deficiency suppresses excitability of nerve cells in the hippocampus. PTZ administration also significantly increased expression of gene and its product of neurotrophic factor BDNF in wild-type hippocampus, whereas octn1-/- exhibited little change in their expression, implying that seizures may be attenuated because the induction of hippocampal BDNF was suppressed by octn1 gene deficit. OCTN1 highly recognizes food-derived antioxidant amino acid ergothioneine (ERGO) as a substrate, and ERGO is present in the most organs including brain. However, seizure score in mice ingested with ERGO-free diet was almost comparable with that in mice with normal one, suggesting that substrate(s) other than ERGO may be involved in PTZ-induced seizure[Conclusions] Gene deficiency of octn1 inhibits the formation of excitatory synapses possibly by suppressing the induction of BDNF and may attenuate PTZ-induced seizure.