公募シンポジウム

公募シンポジウム神経可塑性誘導による回路再編のメカニズム

7月7日（金）　10:40-12:40　Room G 2SY⑥-1 シナプスタンパク質の生物学的相分離による神経可塑性誘導 Induction of neuronal plasticity by biological phase separation of synaptic proteins 実吉　岳郎京都大学大学院医学研究科 Takeo Saneyoshi Dept. of Pharmacol., Kyoto Univ., Kyoto, Japan Plasticity of synaptic structure and function underlies learning and memory. Intracellular signaling during synaptic plasticity is initiated by Ca2+ influx into the spine from NMDA-type glutamate receptors and the subsequent activation of calmodulin-dependent protein kinase 2 (CaMKII). CaMKII is a dodecameric protein kinase that autophosphorylates at T286 to generate autonomous activity, which contributes to synaptic transmission and is required for memory formation. Because of this biochemical property, CaMKII is widely accepted as a memory molecule.Our group and others have reported that CaMKII maintains persistent biochemical activity by interacting with GluN2B or Tiam1 independently of autophosphorylation. In addition, CaMKII brings proteins together at the synapse through liquid-liquid phase separation (LLPS), a phenomenon in which different proteins spontaneously assemble in a cellular compartment known as a membraneless organelle. Therefore, we hypothesize that synaptic plasticity can be manipulated by LLPS of CaMKII at the synapse. In this symposium, I will present about how CaMKII maintains its activity at the synapse using synaptic localization via nanobody of synaptic proteins of the FRET sensor of CaMKII as well as in vitro reconstituted LLPS. Possible high-throughput screening for small molecule manipulation of LLPS will also be discussed.		7月7日（金）　10:40-12:40　Room G 2SY⑥-2 神経回路形成因子LOTUSによるシナプス可塑性誘導 Induction of synaptic plasticity by a neural circuit formation factor LOTUS 川口　祐生^1,2, 西田　遼平², 松林　潤平^1,2, 竹居　光太郎^1,2 1. 横浜市立大学　医学部　臓器再生医学教室　神経再生医学講座, 2. 横浜市立大学大学院　生命医科学研究科 Yuki Kawaguchi^1,2, Ryohei Nishida², Junpei Matsubayashi^1,2, Kohtaro Takei^1,2 1. Lab. for Neural Reg Med, Dept. of Reg Med, Yokohama City Univ. Sch.of Med., Yokohama, Japan, 2. Dept. of Med. Life Sci., Yokohama City Univ. Grad. Sch. of Med. Life Sci., Yokohama, Japan Nogo signaling has been reported to reduce memory via a decreased synaptic density. The lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of Nogo receptor-1. We found that loss of LOTUS impairs memory via decreased synaptic density in the hippocampus. We examined if LOTUS overexpression induced synapse formation and memory. An increased synaptic density was found in the hippocampus of LOTUS-overexpressing transgenic (LOTUS-Tg) mice, and the LOTUS-Tg mice showed enhanced hippocampus-dependent memory. Furthermore, we found that LOTUS expression decreased in the hippocampus of aged mice, and hippocampus-dependent memory formation was reduced in aged wild-type (WT) mice. In contrast, aged LOTUS-Tg mice maintained LOTUS expression and higher dendritic spine density in the hippocampus than aged WT mice. These findings suggest that maintenance of LOTUS expression may suppress age-associated memory dysfunction in aged mice.

7月7日（金）　10:40-12:40　Room G 2SY⑥-3 ニューロモデュレーションによる局所回路可塑性の機序 Mechanisms of local circuit plasticity by neuromodulation 山室　和彦奈良県立医科大学精神医学講座 Kazuhiko Yamamuro Department of Psychiatry, Nara Medical University Today, the number of patients visiting psychiatry continues to increase gradually. Various drug treatments are available for psychiatric disorders, but all have limited effectiveness. Although repetitive transcranial stimulation therapy (rTMS) is indicated for patients who have been refractory to pharmacological treatment for major depressive disorders, the mechanism of rTMS and its effects on symptoms other than depression is not well understood. We used deep brain stimulation (DBS), a neuromodulation technique, to stimulate the medial prefrontal cortex (mPFC) of mice locally because rTMS acts on the whole brain. We tested changes in social behavior, depressive symptoms, activity, and anxiety-related behavior induced by DBS in a restraint stress (RS) model, a social defeat (SD) model, and juvenile isolation (jSI) model. DBS ameliorated depressive symptoms that RS and SD models commonly showed. Also, DBS increased social behavior that jSI and SD models commonly showed. Next, sIPSC frequency to LayerV/VI pyramidal cells was significantly increased by DBS stimulation. In contrast, increased sEPSC and decreased sIPSC frequency were also observed in LayerV/VI parvalbumin interneurons. These results suggest that DBS might affect mPFC local circuits and ameliorate associated behavioral abnormalities in each model mouse.		7月7日（金）　10:40-12:40　Room G 2SY⑥-4 ペリニューロナルネットを操作する手法の確立と神経可塑性の制御への応用 Development of a technique for manipulating perineuronal nets and its application to the regulation of brain plasticity 宮田　真路東京農工大　農学府 Shinji Miyata Grad. Sch. Agr., TUAT During postnatal development, chondroitin sulfate proteoglycans (CSPGs) condense around parvalbumin-expressing inhibitory interneurons (PV cells), forming perineuronal nets (PNNs), a specialized extracellular matrix structure that interdigitates with synaptic contacts. Enzymatic disruption of PNNs with chondroitinase ABC reactivates critical period plasticity in adult animals, indicating that PNN formation is responsible for the closure of the critical period. However, the molecular mechanisms underlying the regulation of the critical period plasticity by PNNs are poorly understood due to the absence of techniques to manipulate these structures. Here we hypothesized that ectopic expression of specific components of PNNs enables the formation of PNNs around non-PV cells. Our findings revealed that aggrecan, a large aggregating CSPG, was predominantly expressed by PV cells in a neuronal activity-dependent manner. The forced expression of GFP-fused aggrecan and link proteins by neocortex-directed in utero electroporation resulted in the ectopic emergence of PNN-like structures around pyramidal neurons. Our study may offer a novel approach to elucidate how PNNs control critical period plasticity.

7月7日（金）　10:40-12:40　Room G 2SY⑥-5 異種感覚可塑性形成におけるグリア細胞の役割 The role of glial cells in cross-modal plasticity 竹田　育子^1,2, 橋本　明香里¹, 竹井　いずも¹, 井上　澪¹, 鏡内　麻以¹, 青山　友紀¹, 和氣　弘明^1,2 1. 名古屋大学　大学院医学系研究科　分子細胞学, 2. 生理学研究所　多細胞回路動態研究部門 Ikuko Takeda^1,2, Akari Hashimoto¹, Izumo Takei¹, Mio Inoue¹, Mai Kagamiuchi¹, Yuki Aoyama¹, Hiroaki Wake^1,2 1. Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan, 2. Division of Multicellular Circuit Dynamics, National Institute for Physiological Sciences, Okazaki, Japan The resulting phenotype by visual loss varies with age - heightened tactile acuity (cross-modal plasticity) before puberty, but visual illusions in adulthood. We investigated the role of glial cells in circuit reorganization of secondary visual cortex (V2L) induced by visual deprivation. We modelled congenital and acquired blindness in 2- week and 5-week old mice, respectively. For microglia, their ablation in 2-week deprived mice abolished the increase in whisker stimulation induced V2L neuronal activity. Mechanistically, this was associated with altered perisynaptic sculpting wherein microglial enwrapping of neuronal somas mediated increased inhibitory synapse stripping. Importantly, this V2L circuit reorganization could be directly linked to cross-modal plasticity as mice showed faster discrimination task learning rates. Notably, 5-week deprived mice also showed altered V2L neuronal activity but no learning rate improvement. For astrocytes in V2L, their numbers, Ca²⁺ activity and synchronicity were all increased in 5-week BD mice despite an overall decrease in V2L neuronal activity. These results suggest that microglia and astrocytes may be differentially recruited following visual deprivation in childhood vs adulthood. Thus, glial cells may play a pivotal role in the age-related divergence in vision loss-induced circuit remodeling phenotypes.