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シンポジウム dystonin 3S6-1 Glial assembly：gliotransmission and pathophysiological consequences Koizumi Schuichi1,2，Shigetomi Eiji1,2，Hirayama Yuri1,3，Morizawa Yosuke1,2，Shinozaki Youichi1,2 1Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi，2CREST, Japan Science and Technology Agency，3Department of Liaison Academy, Faculty of Medicine, University of Yamanashi Glial cells form functional“assembly”, by which they control a broad range of brain functions, especially in the pathophysiological conditions. To assess the operating principle of glial assembly, we have taken two strategies；（1）visualization of glial functions at the interphase of astrocytes, （2）spatiotemporal control of gliotransmission. （1）For visualization of interphase astrocyte, we expressed genetically encoded calcium indicator（GECI）, Lck-GCaMP3 or GCaMP3, into astrocytes. To introduce GECI into astrocytes, we injected adeno-associated viruses with GFAP minimal promoter into the brain or used transgenic mice generated by Cre-loxP mediated recombination. GECI successfully reports numerous calcium signals at processes in acute brain slices. By using these, we found that even very mild ischemic episode（preconditioning；PC）could increase an Ca2+ excitability in interphase glia, which was mediated via P2X7 receptors. This was responsible for induction of ischemic tolerance, a phenomenon that a mild ischemic episode induces resistance to a subsequent severe ischemic injury. We also discuss molecular mechanisms underlying astrocyte-mediated ischemic tolerance. （2）For spatiotemporal control of gliotransmission, we used transgenic mice to suppress or overexpress P2Y1 receptors（or VNUT）in astrocytes. ATP/P2Y1 receptor has a central role in regulation of gliotransmission in astrocytes. Astrocytes overexpressing P2Y1 receptors showed ~3 fold increase in calcium excitability in astrocytes from the dentate gyrus of acute brain slices, which is responsible for synchronization of astrocytic Ca2+ excitabilities. In addition, as for pathophysiological consequences of these, we found that ATP/P2Y1 receptor-mediated signals was required and sufficient for scar formation after traumatic brain injury, leading to neuroprotection against secondary damages of TBI. These strategies should shed light on the unique and novel functions of glial assembly. 3S6-2 Disease-associated modification of hereditary demyelinating disorder-related protein dynamics Miyamoto Yuki，Yamauchi Junji Department of Pharmacology, National Research Institute for Child Health and Development Oligodendrocytes and Schwann cells contribute to producing myelin sheaths in the central nervous system（CNS）and peripheral nervous system（PNS）, respectively. The myelin sheath consists of morphologically differentiated plasma membranes of myelin-forming glial cells. Myelin sheaths not only insulate axons to increase their nerve conduction velocity but also protect them from various external stresses such as physical stress. For this reason, myelin sheaths play essential roles in homeostasis of the nervous system. Therefore, the diseases that affect them, triggering dismyelination and repeated demyelination, cause nerve damage and, in turn, severe CNS or PNS neuropathies. One such disease is Pelizaeus-Merzbacher disease, a rare X-linked recessive disease. This disease is the prototypic hereditary hypomyelinating leukodystrophy（HLD）and is now designated as HLD1（OMIM No. 312080）. The responsible gene is plp1, and the disease can be caused by a variety of alterations to it such as missense mutations and gene multiplication. Through technological advances, including next-generation sequencing technology, different somatic genes have been identified to date as the HLD responsible genes（from the hld2 to hld9 or hld10 genes）；nevertheless, it still remains to be understood how their alterations affect the properties of their protein products. Herein, we are going to talk about our recent studies of whether or how some HLD-associated mutated proteins cause their diseases. Also, we will discuss about their possible therapeutic drug targets. 3S6-3 Emerging concept of primary microgliopathy in the pathogenesis of neurological diseases Ikeuchi Takeshi Department of Molecular Genetics, Brain Research Institute, Niigata University Microglia are derived from primitive macrophages in the yolk sac and ubiquitously distributed in the brain. They are critical effectors and regulators of changes in CNS homeostasis during development and in healthy and pathological conditions. Numerous studies over the last decade have suggested that microglia activation reactively induced by neurodegeneration and neuroinflammation substantially modulate disease progression and severity in various neurological disorders including Alzheimer’s disease and amyotrophic lateral sclerosis（ALS）. Several lines of evidence has recently suggested that primary microglial dysfunction essentially contributes to the pathogenesis of the neurological diseases predominantly affecting the cerebral white matter. This condition is now recognized as primary microgliopathy. Hereditary diffuse leukoencephalopathy with spheroids（HDLS）and Nasu-Hakola disease（NHD）predominantly are considered as primary microgliopathies. The causative genes for HDLS and NHD are colony stimulating factor-1 receptor（CSF-1R）and DAP12/TREM2, respectively, both of which are strongly expressed in microglia. We previously showed that HDLS is caused by haploinsufficiency of CSF-1R and loss of CSF-1R-mediated signaling. The neuropathological examination revealed that density of microglia decreased in HDLS brain. Moreover, individual microglia in HDLS brain demonstrated their characteristic morphology with thin processes and many knotlike structures. These findings have suggested that microglia dysfunction associated with loss of CSF-1R signaling play an essential role in the phathogenesis of HDLS. Considering that microglia are important players in the maintenance and plasticity of neuronal circuits, contributing to the protection and remodeling of synapse, microglial disability and dysfunction may be relevant to the axonal and myelin damages characteristically observed in the white matter. These pathological events in primary microgliopathies may shed new light on our understanding of unrecognized physiological role（s）of microglia. 3S6-4 Analyses of neuronal and glial cell phenotype of dystonia musculorum mice Takebayashi Hirohide Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University Mutation of the Dst gene encoding dystonin, a cytoskeletal linker protein, in mice results in a movement disorder, termed dystonia musculorum（dt）, which shows dystonia and cerebellar ataxia, in addition to sensory neuron degeneration. Both the pathological feature and the molecular basis for the dt phenotype are not fully understood. In the present study, we investigated neuronal and glial phenotypes in the central nervous system（CNS）of the dt mice. We found abnormal staining pattern of neurofilaments（NFs）, densely immunoreactive cell bodies and thick axons in the CNS of dt mice, such as in the vestibular and reticular nucleus of brainstem, some of which are responsible for motor functions. We also found reduced glial cell proliferation in the CNS of dt mice. We will discuss how much these abnormalities contribute to the dt phenotype.