一般口演（Oral）

Oral Psychiatric Disorders: Neural Circuit 一般口演精神疾患：神経回路

7月26日（金）15:10～15:25　第8会場（朱鷺メッセ　3F　303+304） 2O-08a1-1 Cadherin 13 interacts with integrin beta-1 and integrin beta-3 to regulate inhibitory synaptic function in a human neuronal model Britt Mossink（Mossink Britt）^1,3，Jon-Ruben van Rhijn（Rhijn Jon-Ruben）^1,3，Martijn Selten（Selten Martijn）^2,3，Katrin Linda（Linda Katrin）^1,3，Eline van Hughte（Hughte Eline van）^1,3，Jason Keller（Keller Jason）^1,3，Jitske Bak（Bak Jitske）^2,3，Monica Frega（Frega Monica）^1,3，Dirk Schubert（Schubert Dirk）^2,3，Nael Nadif Kasri（Nadif Kasri Nael）^1,2,3 ¹Department of Human Genetics, Radboudumc, Nijmegen ²Department of Cognitive Neurosciences, Radboudumc, Nijmegen ³Donders Institute for Brain Cognition and Behaviour, Nijmegen The brain is a complex neural network that requires a precisely tuned interplay of excitatory and inhibitory signals in order to function. Disruptions in synaptic connectivity, in particular the balance between excitation (E) and inhibition (I), have been shown to underlie neurodevelopmental disorders (NDDs). However, the mechanisms underlying this coordination remain elusive. One gene that is implicated NDDs is Cadherin 13 (CDH13). CDH13 is a special member of the cadherin superfamily since it lacks a transmembrane-and intracellular domain, and instead is anchored to the membrane via a glycosylphosphatidylinositol (GPI) anchor. Because of this relatively weak connection to the outer membrane, CDH13 has been proposed to serve as a regulatory protein rather than an adhesion molecule. In humans, dysregulations of CDH13 has been linked to attention-deficit/hyperactivity disorder and comorbid disorders such as autism and schizophrenia. Studies in mice have showed that CDH13 is localized at the inhibitory presynapse of parvalbumin and somatostatin interneurons, and when knocked out in mice results leads to increased inhibitory, but not excitatory drive onto hippocampal CA1 pyramidal neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. To understand the function of CDH13 in human neurons, we generated both GABAergic and Glutamatergic neurons via controlled differentiation of Induced Pluripotent Stem Cells (hIPSC). Using RNA interference, we reduced CDH13 expression in GABAergic neurons. We investigated neuronal network communication using of Micro-Electrode Arrays, whereas on a single-cell level, either inhibitory or excitatory synaptic transmission was assessed using whole-cell patch-clamp recordings. Our data shows that CDH13 knockdown in human GABAergic neurons increases inhibitory control on glutamatergic neurons on MEA. Moreover, cell-adhesion assay revealed a heterophilic interaction between CDH13 with both ITGB1 and ITGB3. Interestingly, coexpression of GABAA receptor alpha1 with ITGB3, but not with ITGB1, abolished aggregation in the cell-adhesion essay. This indicates that ITGB1 and ITGB3 play an opposite role in the regulation of inhibitory synaptic strength via interaction with CDH13. In summary, these results point towards an important role for CDH13 in inhibitory synapses via CDH13- ITGB1 /ITGB3 interaction, which could be critical in the maintenance of the E/I balance.		7月26日（金）15:25～15:40　第8会場（朱鷺メッセ　3F　303+304） 2O-08a1-2 オキシトシンが制御する共感性の神経回路の解明 Saori Yada（矢田紗織），Kengo Horie（堀江謙吾），Shizu Hidema（日出間志寿），Katsuhiko Nishimori（西森克彦）東北大院農応用生命科学分子生物 Social behavior to communicate with others is essential for the survival for organisms including human. Empathy is a mental function that shares emotional state with others, and it is essential as a motivation for causing social behaviors that help other people such as compassion and comfort. Oxytocin (Oxt) is a peptide synthesized in the paraventricular nucleus and the supraoptic nucleus and is known to be involved in social behaviors and empathy. Recent studies have focused on Oxt and its receptor (Oxtr) as therapeutic drug candidates for mental disorders, especially social disorder symptoms of autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by repetitive behaviors and deficits in social behavior and empathy, while the etiology and treatments for ASD are poorly understood. Therefore, it is strongly expected that the fundamental elucidation of the neural mechanisms of the sociality by Oxt/Oxtr system. It is also necessary to investigate the mechanism of empathy which is the root of social behavior, because it is thought that neuroscience study of empathy is widely applicable to treatment of many mental diseases including ASD. However, the empathic neural circuits regulated by Oxt/Oxtr have been still unknown. In this study, we researched how the Oxt/Oxtr system controls empathy. We analyze brain regions and neural circuits of Oxtr+ neurons involved in empathy in the whole brain and aim to contribute to treatment of sociality of mental disorders including ASD in the future. Here we performed empathic behavioral tests for Oxt/Oxtr genetic modified rodents, and analyzed the relationship between Oxtr+ neurons and empathy. We revealed that the Oxt/Oxtr signals are important for empathy, and identified the brain regions related to empathic behavior in the whole brain.

7月26日（金）15:40～15:55　第8会場（朱鷺メッセ　3F　303+304） 2O-08a1-3 統合失調症とそのモデル動物における聴覚皮質過活動の分子プロファイル Yuriko Iwakura（岩倉百合子）¹，Norikazu Hara（原範和）²，Ryouka Kawahara（川原玲香）³，Hidekazu Sotoyama（外山英和）¹，Hiroyoshi Inaba（稲葉洋芳）¹，Yutaro Kobayashi（小林雄太朗）¹，Eiko Kitayama（北山栄子）¹，Akiyoshi Kakita（柿田明美）⁴，Hitoshi Takahashi（高橋均）⁴，Yasuto Kunii（國井泰人）^5,6，Mizuki Hino（日野瑞城）⁵，Hirooki Yabe（矢部博興）⁵，Takeshi Ikeuchi（池内健）²，Satoshi Kida（喜田聡）⁷，Hiroyuki Nawa（那波宏之）¹ ¹新潟大脳研分子神経生物学 ²新潟大脳研遺伝子機能解析学 ³東京農業大生物資源ゲノム解析セ ⁴新潟大脳研病理学 ⁵福島県立医大医神経精神医 ⁶福島県立医大会津医療セ ⁷東京農業大生命科学バイオサイエンス Epidermal growth factor (EGF) family proteins and their receptors (ErbBs) are widely expressed in the central nervous system and suggested to associate with a schizophrenia risk and/or its neuropathology. We previously reported that the rodent models exposed to EGF during neonatal period show abnormalities in molecular neuropathology and cognitive behaviors relevant to schizophrenia, such as GABAergic deficits and social interaction decline. The fundamental auditory function of this model is also impaired as reported in patients with schizophrenia, including prepulse inhibition, auditory evoked potentials, mismatch negativity (MMN) and auditory brainstem response. In this study, we measured gene and protein expression in the primary auditory cortex of this rat model, and compared with the RNA-Seq data of postmortem superior temporal cortex. The gene expression of fos and egr1 (zif268), which are neuronal activity markers, was elevated in the model rats. This phenomenon was reproduced and confirmed at the protein level. The microglial marker, Iba1, was also region-specifically increased in these rats. The auditory activation of the rats appeared not to stem from their self-vocalization because no abnormality was observed in their ultrasonic vocalizations. Similar changes in mRNA profile of this rat were observed in that from the postmortem superior temporal cortex including the primary auditory cortex of patients with schizophrenia. The increased expression of egr1, 2, 4 and fos gene, mRNA levels of microglial marker CD40 were elevated in postmortem auditory cortex of patients with schizophrenia. Perineuronal nets (PNNs) are formed on GABAergic neurons along with neuronal development, and are involved in their synaptic maturation and stabilization. In another rodent model, EGF-overexpressing transgenic (EGF-Tg) mice, the amounts of 4-sulfated chondroitin and 6-sulfated chondroitin in the auditory cortex, which are components of perineuronal nets, were different from those in the wild type mice. These agreement between the results from model animals and postmortem brains of patients confirm the validity of this disease model and suggest the contribution of the hyperactivity/abnormal activity in the auditory cortex to schizophrenia.		7月26日（金）15:55～16:10　第8会場（朱鷺メッセ　3F　303+304） 2O-08a1-4 社会性ストレス応答における温度受容体TRPV4の関与 Yutaka Hoshi（星雄高）¹，Koji Shibasaki（柴崎貢志）²，Yuji Ikegaya（池谷裕二）¹，Ryuta Koyama（小山隆太）¹ ¹東京大院薬薬品作用 ²群馬大院医分子細胞生物 Social defeat stress is known to increase the core body temperature of stressed animals; however, it remains unknown whether and how the stress-induced elevation in the core body temperature modifies animal behaviors. Here we used a mouse model of social defeat stress and examined the mechanisms that link stress-induced hyperthermia and abnormal behaviors. Social defeat stress induced depressive- and anxiety-like behaviors in mice, as assessed by the tail suspension and elevated plus maze tests. The rectal temperature of stressed mice was significantly increased compared to control. This elevation in the rectal temperature was maintained at least for four weeks after the final stress experience. Next, we examined the cellular and molecular mechanisms how the stress-induced hyperthermia modifies the behaviors of stressed mice, specifically focusing on the involvement of transient receptor potential vanilloid 4 (TRPV4), a thermosensitive channel which is highly expressed in the brain. We found that stress-induced depressive or anxiety-like behaviors were not observed in TRPV4 knockout (KO) mice, although stress-induced hyperthermia was maintained in TRPV4KO mice. These results suggest that TRPV4 mediates stress-induced behaviors, probably activated by temperature elevation. Next, we immunohistochemically investigated the expression property of TRPV4 in the hippocampus of stressed mice, because stress-induced behaviors have been suggested to modify adult hippocampal neurogenesis. We found that TRPV4 was preferentially localized in the nestin-positive radial glia-like cells, a cellular population from which newborn cells arise, in the dentate gyrus. We further found that the expression of nestin was decreased in stressed mice and this effect was blocked in TRPV4KO mice. These results suggest the involvement of hyperthermia and TRPV4 in stress-induced behaviors presumably through the modification of adult neurogenesis.