Symposium

Symposium 2 Autism Research (Basic Science) シンポジウム2 自閉症学研究（基礎）

SY2-1 Exercise reverses behavioral and synaptic abnormalities after maternal inflammation 母体感染による仔のシナプス異常と自閉症様行動の運動による改善 Koyama Ryuta（小山隆太），安藤めぐみ，池谷裕二 Lab. Chem. Pharmacol., Grad. Sch. Pharmaceut. Sci., Univ. Tokyo Abnormal behaviors in individuals with neurodevelopmental disorders are generally believed to be irreversible. Here, we show that voluntary wheel running ameliorated the abnormalities in sociability, repetitiveness, and anxiety observed in a mouse model of a neurodevelopmental disorder induced by maternal immune activation (MIA). Exercise activated a portion of dentate granule cells, normalizing the density of hippocampal CA3 synapses, which was excessive in the MIA-affected offspring. The synaptic surplus in the MIA offspring was induced by deficits in synapse engulfment by microglia, which was normalized by exercise through microglial activation. Finally, chemogenetically induced activation of granule cells promoted the engulfment of CA3 synapses. Thus, our study proposes a novel role of voluntary exercise in the modulation of behavioral and synaptic abnormalities in neurodevelopmental disorders.		SY2-2 Approaching autism from molecules 分子から自閉症に迫る Usui Noriyoshi（臼井紀好）^1,2 ¹CentMeRE, Grad Sch Med, Osaka Univ, Osaka, Japan ²Dept Neurosci Cell Biol, Grad Sch Med, Osaka Univ, Osaka, Japan The evolution of the human brain has led to an increased vulnerability to both neurodevelopmental and psychiatric disorders like autism and schizophrenia. These disorders include phenotypes such as dysfunction in social communication and language. It is therefore interesting that the implementation of spoken language in humans as a communication skill is perhaps the one of unique evolved characteristic of humans compared to other primates. However, while the molecular mechanisms underlying the circuitry of higher brain functions including sociality and language, and as well as autism-related behaviors in humans have likely expanded upon evolutionarily conserved circuitry most of these mechanisms and circuitry remain unknown. Here we show and discuss our latest findings of the genes related to autism as an example how we can apply to the basic science research of autism and brain development by focusing on the molecules.

SY2-3 Disrupted immune system and abnormal myelination in autism spectrum disorder 自閉スペクトラム症の免疫異常とミエリン形成障害 Makinodan Manabu（牧之段学） Dept. of Psychiatry, Nara Medical University Recent studies indicate disruptions of immune system in patients with autism spectrum disorder (ASD); elevated expressions of proinflammatory cytokines, increased number of monocytes, and activation of microglia in the brain. On the other hand, myelin abnormalities are also recognized as part of pathobiology of ASD, but the mechanism remains to be elucidated. Interestingly, it has been known that immune activities strongly affect myelination although it remains unknown whether myelination has any effects on immune systems. Based on the findings from other groups, IL-6 expressions in the blood and brain of ASD are increased, and we found high expression of IL-6 disturbs myelination in the prefrontal cortex (mPFC) of mice, leading us to investigate the relationships of IL-6 expression and myelination in the mPFC-related tract, uncinate fasciculus, which is one of the most vulnerable brain regions in patients with ASD. Analyses using Diffusion Tensor Imaging demonstrated that high IL-6 expression in M1 macrophage, not M2, correlates with low fractional anisotropy. Together, these results suggest that disturbed immune system may be a cause of myelin abnormalities in the uncinate fasciculus of ASD.		SY2-4 Autism model mice with 15q11-13 duplication show severe developmental abnormalities 染色体15q11-13に部分重複を持った自閉症モデルマウスは重篤な低成長を伴う Nakatani Jin（中谷仁）¹，豊田太²，郷康弘⁴，堀家慎一⁵，小山なつ³，等誠司³，内匠透⁶，田中秀和¹ ¹Dept of Pharmacology, Ritsumeikan Univ ²Dept Cell Physiology, Shiga Univ of Medical Science ³Dept Integrative Physiology, Shiga Univ of Medical Science ⁴Dept Brain Sciences, National Institute of Natural Sciences ⁵Advanced Science Research Center, Kanazawa Univ ⁶Brain Science Institute, RIKEN 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 more sever social deficits than Dp in the three chamber social interaction test. Electrophysiological studies showed DpDp had severe heart defects. These data indicate that DpDp mice have both developmental and behavioral abnormalities, including heart failures.