指定口演

将来計画委員会推奨シンポジウム（公募）：若手研究者が挑むグリア-神経細胞間コミュニケーションの研究最前線 Symposium : New Insights in Understanding Glia-Neuron Communication by Young Investigators

2020/9/12　9:00～9:20　Zoom B SW-01 アストロサイト性虚血耐性の分子メカニズム解析 Mechanisms of astrocyte-mediated ischemic tolerance 平山友里^1,2、小泉修一²、安西尚彦¹ 1. 千葉大学、2. 山梨大学 Yuri Hirayama^1,2, Schuichi Koizumi², Naohiko Anzai¹ 1. Chiba Univ., 2. Univ. Yamanashi A sub-lethal ischemic episode (PC: preconditioning) protects neurons against a subsequent lethal ischemic injury. This phenomenon is known as ischemic tolerance. We previously showed that PC caused activation of astrocytes and a subsequent upregulation of P2X7 receptors, activation of which induced ischemic tolerance via upregulation of HIF-1α in astrocytes. P2X7 receptor requires much higher concentrations of extracellular ATP (eATP) for its activation. However, the PC-evoked increase in eATP is not enough to activate P2X7 receptor. It has been reported that NAD⁺ at lower eATP could induce sustained activation of P2X7 receptor via ADP-ribosyltransferase 2 (ARTC2)-catalyzed ADP-ribosylation in peripheral immune cells. Here, we show that astrocytes possess this signaling pathway, thereby leading to P2X7-mediated ischemic tolerance. In the in vitro experiments using primary astrocyte culture, we found that even lower eATP could activate P2X7 receptor and subsequent HIF-1α production if NAD⁺ is present, which was abolished by P2X7 receptor antagonist, suggesting that astrocytes should possess the NAD⁺/ARTC2/P2X7 signaling pathway and sensitize P2X7 receptor to ATP by these signals. In the in vivo experiments using a focal cerebral ischemia model of mice, we also found that PC activated the NAD⁺/ARTC2/P2X7 signaling pathway in astrocytes but not in microglia because of their lacking of ARTC2. Importantly, inhibition of ARTC2 with s+16a suppressed the astrocytic P2X7 receptor-mediated ischemic tolerance by PC. Taken together, the NAD⁺/ARTC2 signal should have a key role that allows astrocytes to induce P2X7 receptor/HIF-1α-mediated ischemic tolerance.		2020/9/12　9:20～9:40　Zoom B SW-02 慢性掻痒におけるアストロサイト活性化機構とその役割 Mechanism of astrocytic activation and its role in chronic itch 白鳥美穂¹ 1. 九州大学大学院薬学研究院 Miho Shiratori-Hayashi¹ 1. Graduate School of Pharmaceutical Sciences, Kyushu University Chronic itch is an intractable symptom of inflammatory skin diseases, such as atopic and contact dermatitis, but the underlying mechanism is poorly understood. We previously demonstrated that STAT3-dependent reactive astrocytes and subsequent LCN2 increase in the spinal dorsal horn play a crucial role in spinal cord central sensitization of itch and progression of chronic itch associated with dermatitis. Recently, we found the mechanisms of astrocytic STAT3 activation via calcium signals caused by a primary afferent sensory neuron-derived factor under chronic itch conditions. In this presentation, I will show the mechanisms of astrocytic activation and its role in chronic itch.

2020/9/12　9:40～10:00　Zoom B SW-03 アストロサイトGPCRシグナリングが生み出す回路・行動ダイナミクス Exploring astrocyte GPCR signaling in neural circuits and animal behavior 長井淳¹、Abha K Rajbhandari¹、Mohitkumar R Gangwani¹、Ayaka Hachisuka¹、Giovanni Coppola¹、Sotiris C Masmanidis¹、Michael S Fanselow¹、Baljit S Khakh¹ 1. カリフォルニア大学ロサンゼルス校 Jun Nagai¹, Abha K Rajbhandari¹, Mohitkumar R Gangwani¹, Ayaka Hachisuka¹, Giovanni Coppola¹, Sotiris C Masmanidis¹, Michael S Fanselow¹, Baljit S Khakh¹ 1. University of California, Los Angeles A central goal in brain science is to understand how multiple types of brain cells dynamically interact with each other and how they contribute to nervous system function and dysfunction. Astrocytes tile the entire central nervous system and display structural and functional interplay with neurons, other glial cells and blood vessels with their myriad fine processes. However, the field lacks detailed understanding of how the interactions between astrocytes and neurons are consequential in health and disease. We will report the latest insights on astrocyte roles in the adult neural circuits, by using multiple integrated approaches, including calcium imaging, electrophysiology, optogenetics, pharmacogenetics, animal behavioral tests, RNA-seq and new astrocyte manipulation tools that we recently developed. We will first describe mechanisms by which neurons and astrocytes bi-directionally communicate in the striatum. We found striatal neurons triggered astrocyte signaling via G_i-coupled GABA_B receptors, and that such astrocyte G_i-GPCR signaling resulted in overt behavioral alterations in mice consistent with hyperactivity and disrupted attention. The underlying mechanism involved synaptic plasticity mediated by re-activation of astrocyte developmental synaptogenic cue thrombospondin-1 (TSP1). In addition, we will report validation work for a new non-invasive and astrocyte-selective tool for attenuating astrocyte G_q-GPCR signaling in vivo. Taken together, our findings show that signaling from astrocytes to neurons is sufficient per se to alter synapses, circuits and behavior in adults. We also provide new tools to study such astrocyte-neuron dynamics.		2020/9/12　10:00～10:20　Zoom B SW-04 化学遺伝学的技術による三者間シナプスの空間的分子ネットワークプロファイリング Chemico-genetic discovery of molecules underlying tripartite-synaptic function in vivo 髙野哲也¹ 1. 慶應義塾大学 Tetsuya Takano¹ 1. Keio University Neuronal synapses are intimately ensheathed by abundant astroctytic perisynaptic processes, which is critical for synapse formation and function. In contrast to well-studied neuronal synaptic compartments, however, the molecular mechanisms of how astrocytic perisynaptic structures govern neuronal synapses remain ill-defined. Here, we develop a new in vivo chemico-genetic approach, iBioID, to identify the molecules at astrocyte-synapse junctions in vivo. We identify more than 100 proteins enriched at astrocyte-neuronal junctions. We find novel adhesion molecules highly expressed in cortical astrocytes whose deletion dramatically reduces inhibitory synapse number and function. Thus, our results present a proteomic framework for how astrocytes interface with neurons. Moreover, they reveal a mechanism of how astrocytes orchestrate GABAergic synapse formation and function via a coordinated tripartite synaptic chemo-affinity code.

2020/9/12　10:20～10:40　Zoom B SW-05 モチベーションや快楽行動を司る分子基盤 Transcriptional mechanisms underlying stress-induced anhedonia-like behavioral symptoms 谷口誠¹、Siemsen Benjamin¹、Kumar Jaswinder ²、Carter Jordan ¹、Pilling Sara¹、Hughes Brandon¹、Brace Emma¹、Wood Isabel ¹、Scofiled Michael¹、Cowan Christopher¹ 1. MUSC、2. UTSW MAKOTO TANIGUCHI¹, Benjamin Siemsen¹, Jaswinder Kumar², Jordan Carter¹, Sara Pilling¹, Brandon Hughes¹, Emma Brace¹, Isabel Wood¹, Michael Scofiled¹, Christopher Cowan¹ 1. MUSC, 2. UTSW In susceptible individuals, the experience of stressful life events can suppress the future ability to experience pleasure, reduce motivation for reward pursuit. Deficits in the reward-related behavior, or anhedonia, is a key feature of the diagnosis of Major Depressive Disorder (MDD) and is strongly associated with the predicted severity and persistence of the disorder. In patients suffering from stress-related mental illnesses and MDD, and in several preclinical animal models, there are enduring changes observed in the prefrontal cortex (PFC) activity and E/I synapse balance, and restoration of PFC E/I balance has anti-depressant effects. Several preclinical depression models have linked chronic pathological stress experiences with changes in mPFC gene expression, epigenetic modifications to DNA and histones, dysfunction of neuronal circuits, and persistent deficits in reward-related behaviors. Physical or emotional stress alters the expression of several transcription factors, including activity-dependent immediate early genes (IEGs). We recently found that the activity-regulated transcription factor, Neuronal PAS domain protein 4 (NPAS4), is transiently induced in the mPFC by stress. NPAS4 is reported to modulate excitatory and inhibitory synapses and synaptic transmission, and as such, is well-positioned to mediate stress-induced changes in neural circuitry and stress-regulated behavior. In this symposium, we discuss the role and regulation of mPFC NPAS4 in the chronic stress-induced changes in social, natural reward preference and motivation, and anxiety-like behaviors.