Symposia

Symposia Next generation symposium by alumni of the Educational Seminars for Young Researchers ②【physiology and diseases】／若手育成セミナー出身者による次世代シンポジウム②【生理・疾患】

2S5-1 The role of region-specific spinal dorsal horn astrocytes in sensory information processing Yuta Kohro¹，Ryuichi Katsuragi¹，Takaaki Oka¹，Sho Muneta¹，Ryoichi Tashima¹，Hidetoshi Tozaki-Saitoh¹，Kazuhide Inoue²，Makoto Tsuda¹ ¹Dept. Life-Innov., Grad. Sch. Pharm. Sci., Kyushu Univ.，²Dept. Mol. Syst. Pharmacol., Grad. Sch. Pharm. Sci., Kyushu Univ. Neuropathic pain is caused by a lesion or malfunction of the central nervous system, which is often resistant to current therapeutic treatment. Accumulating evidence indicates that spinal dorsal horn (SDH) astrocytes become reactive states after nerve injury and play a pivotal role in the maintenance of neuropathic pain. However, whether SDH astrocytes activity changes sensory information processing in normal condition is unknown because a lack of tools for modulating activity of SDH astrocytes in vivo. First, we established a minimally invasive method of the microinjection of a substance into the SDH. Using this technique, we microinjected recombinant adeno-associated virus (rAAV) including a GFAP promoter and a gene encoding the excitatory DREADD hM3Dq and successfully expressed hM3Dq in SDH astrocytes. We found that selective stimulation of SDH astrocytes by CNO induced transient mechanical hypersensitivity without changing spontaneous pain behaviors and sensitivity to other noxious stimuli. Furthermore, we also revealed in a transgenic mouse line that astrocytes in superficial, but not deeper lamina of the SDH are the responsible cell subpopulation for the CNO-induced transient mechanical hypersensitivity. Our results uncover a novel function of subpopulation of SDH astrocytes in modality-specific somatosensory processing.		2S5-2 Involvement of non-vesicular transport type of autophagy in encephalitis virus replication Yuuki Fujiwara¹，Kazuki Oroku²，Yoshiyuki Oshima²，Yoshiaki Furuya²，Katsunori Hase¹，Viorica Raluca Contu¹，Masayuki Takahashi¹，Chihana Kabuta¹，Tetsuo Sato²，Nobuyuki Tsutsumi²，Keiji Wada¹，Tomohiro Kabuta¹ ¹Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry，²Nippon Institute for Biological Science Degradation of unnecessary or toxic materials within cells including neurons by lysosomes plays crucial rolls in maintenance of intracellular environment, and thus, is important for physiological homeostasis. For example, dysfunction of RNase T2, a major ribonuclease in lysosomes, causes leukoencephalopathy. Systems in which intracellular materials are delivered into lysosomes and degraded are called autophagy in the broad sense. Mutations in genes related to macroautophagy, the most well-defined type of autophagy, have been reported to cause neurodegenerative disorders in human. We have previously identified a novel type of autophagy, RNautophagy/DNautophagy (RDA), where lysosomes directly take up and degrade RNA and DNA without involvement of vesicular transport. However, physiological and pathophysiological significance of these pathways remained largely elusive. Viruses produce various kinds of nucleic acids in host cells upon replication. We hypothesized that RDA can suppress virus replication by degrading such viral nucleic acids. In this talk, I will present our recent advances in the study on anti-viral role of the RDA against encephalitis virus.

2S5-3 Three dimensional ultrastructure of new neurons migrating in the normal and injured adult brain Mami Matsumoto¹，Masato Sawada¹，Naoko Kaneko¹，Huy Bang Nguyen²，Truc Quynh Thai²，Natsuko Kumamoto³，Shinya Ugawa³，Nobuhiko Ohno⁴，Kazunobu Sawamoto^1,5 ¹Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan，²Division of Neuronal Development and Regeneration, National Institute for Physiological Sciences, Okazaki, Aichi, Japan，³Department of Anatomy and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan，⁴Division of Histology and Cell Biology, Department of Anatomy, Jichi Medical University School of Medicine, Tochigi, Japan，⁵Division of Neuronal Development and Regeneration, National Institute for Physiological Sciences, Okazaki, Aichi, Japan In the adult rodent brain, new neurons are generated from neural stem cells in the ventricular-subventricular zone (V-SVZ). Under physiological conditions, these new neurons form chain-like cell aggregates and migrate along the rostral migratory stream toward the olfactory bulbs, where they are integrated into pre-existing neural network. Within chains, migrating new neurons show saltatory movement along their neighboring ones, in which they extend long leading process followed by somal translocation. Following brain injuries, V-SVZ-derived new neurons migrate in chains toward the lesion and differentiate into mature neurons, suggesting that chain formation is important for migration of new neurons in the adult brain. However, how cellular adhesion between new neurons during chain migration is regulated remains unknown. To observe the cellular adhesion in chain-forming new neurons, we performed electron microscopic analyses. Three-dimensional distribution of cellular adhesion between migrating new neurons visualized using serial block-face scanning electron microscopy suggest that cellular adhesion is dynamically controlled during their saltatory movement. Under transmission electron microscopy, neuronal plasma membrane showed three different types of contacts with the neighboring neurons, adherens junction-like structures, non-specialized contacts, and open extracellular spaces, whose compositions were distinct between the leading process and soma. Furthermore, chain morphology and cellular adhesion patterns between new neurons were altered in the injured brain, suggesting that surrounding microenvironment affects chain migration. Taken together, these results suggest the importance of regulation of cellular adhesion in neuronal chain migration in the adult brain.		2S5-4 Generation of Animal Models and Development of Anti-Dementia Medicines Tomohiro Umeda Department of Translational Neuroscience, Osaka City University Graduate School of Medicine For dementia research, we generated 2 types of mouse model. One is APP_OSK mice, a model of Aβ oligomers representing Alzheimer’s disease, generated by introducing human APP with the Osaka mutation (E693Δ; APP_OSK). The mice display Aβ oligomer accumulation at 8 months and many other neuropathologies except senile plaques. The other is tau609/784 mice, a model of tauopathy representing frontotemporal dementia, generated by introducing human tau with intron sequences. The mice express both 3R and 4R human tau, but 4R tau becomes dominant in adult age by the presence of intronic 16C→T mutation in tau intron 10. This imbalanced expression causes various tau pathologies from 6 months.For passive immunotherapy of tauopathy, we decided to develop new anti-tau antibodies. By the screening in brain sections of tau609/784 mice, we selected pSer413 as a target epitope. We generated monoclonal antibodies and injected one of them, Ta1505, into aged tau609/784 mice intraperitoneally once a week for 1 month. Ta1505 significantly improved memory and reduced tau pathologies, indicating that pSer413 is a good target in the treatment of tauopathy.Then we moved to new research to explore preventive medicines for dementia with a broad spectrum of anti-oligomer activity. We found that an antibiotic rifampicin has potent activities against the accumulation and toxicity of Aβ oligomers in cell culture. Under cell-free conditions, rifampicin inhibited the oligomer formation of Aβ, tau, and α-synuclein. When orally administered to aged APP_OSK and tau609 mice for 1 month, rifampicin reduced the levels of Aβ oligomers and tau oligomers, respectively, and improved memory of the mice. Our results indicate that rifampicin could be a promising, ready-to-use medicine for the prevention of dementia.