9 results on '"Kunimichi Suzuki"'
Search Results
2. In vivo Two-Photon Imaging of Anesthesia-Specific Alterations in Microglial Surveillance and Photodamage-Directed Motility in Mouse Cortex
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Weilun Sun, Kunimichi Suzuki, Dmytro Toptunov, Stoyan Stoyanov, Michisuke Yuzaki, Leonard Khiroug, and Alexander Dityatev
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microglia ,motility ,two-photon imaging ,anesthesia ,isoflurane ,ketamine ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Two-photon imaging of fluorescently labeled microglia in vivo provides a direct approach to measure motility of microglial processes as a readout of microglial function that is crucial in the context of neurodegenerative diseases, as well as to understand the neuroinflammatory response to implanted substrates and brain-computer interfaces. In this longitudinal study, we quantified surveilling and photodamage-directed microglial processes motility in both acute and chronic cranial window preparations and compared the motility under isoflurane and ketamine anesthesia to an awake condition in the same animal. The isoflurane anesthesia increased the length of surveilling microglial processes in both acute and chronic preparations, while ketamine increased the number of microglial branches in acute preparation only. In chronic (but not acute) preparation, the extension of microglial processes toward the laser-ablated microglial cell was faster under isoflurane (but not ketamine) anesthesia than in awake mice, indicating distinct effects of anesthetics and of preparation type. These data reveal potentiating effects of isoflurane on microglial response to damage, and provide a framework for comparison and optimal selection of experimental conditions for quantitative analysis of microglial function using two-photon microscopy in vivo.
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- 2019
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3. A synthetic synaptic organizer protein restores glutamatergic neuronal circuits
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A. Radu Aricescu, Yuki Morioka, Yuka Takeuchi, Tatsuya Shimada, Oleg Senkov, Rahul Kaushik, Kosei Takeuchi, Michisuke Yuzaki, Hiroyuki Sasakura, Stoyan Stoyanov, Alexander Dityatev, Maura Ferrer-Ferrer, Kunimichi Suzuki, Masashi Ikeno, Eriko Miura, Amber J. Clayton, Keiko Matsuda, Wataru Kakegawa, Veronica T. Chang, Masahiko Watanabe, Jonathan Elegheert, Inseon Song, Shintaro Otsuka, and Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Nervous system ,chemistry [Recombinant Proteins] ,drug effects [Synapses] ,Hippocampus ,therapy [Cerebellar Ataxia] ,Mice ,0302 clinical medicine ,Postsynaptic potential ,drug effects [Spine] ,ComputingMilieux_MISCELLANEOUS ,Multidisciplinary ,Glutamate receptor ,therapeutic use [Protein Precursors] ,genetics [Receptors, Glutamate] ,therapeutic use [Nerve Tissue Proteins] ,Motor coordination ,chemistry [Protein Precursors] ,medicine.anatomical_structure ,Excitatory postsynaptic potential ,pharmacology [Recombinant Proteins] ,Ionotropic effect ,pharmacology [C-Reactive Protein] ,Biology ,Neurotransmission ,03 medical and health sciences ,Glutamatergic ,Protein Domains ,medicine ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,therapeutic use [Recombinant Proteins] ,therapy [Alzheimer Disease] ,drug effects [Neural Pathways] ,therapeutic use [C-Reactive Protein] ,metabolism [Receptors, AMPA] ,Mice, Mutant Strains ,Mice, Inbred C57BL ,pharmacology [Protein Precursors] ,Disease Models, Animal ,030104 developmental biology ,HEK293 Cells ,ddc:320 ,pharmacology [Nerve Tissue Proteins] ,chemistry [Nerve Tissue Proteins] ,Neuroscience ,030217 neurology & neurosurgery ,chemistry [C-Reactive Protein] ,physiology [Spine] - Abstract
Synthetic excitatory synaptic organizer The human brain contains trillions of synapses within a vast network of neurons. Synapse remodeling is essential to ensure the efficient reception and integration of external stimuli and to store and retrieve information. Building and remodeling of synapses occurs throughout life under the control of synaptic organizer proteins. Errors in this process can lead to neuropsychiatric or neurological disorders. Suzuki et al. combined structural elements of natural synaptic organizers to develop an artificial version called CPTX, which has different binding properties (see the Perspective by Salinas). CPTX could act as a molecular bridge to reconnect neurons and restore excitatory synaptic function in animal models of cerebellar ataxia, familial Alzheimer's disease, and spinal cord injury. The findings illustrate how structure-guided approaches can help to repair neuronal circuits. Science , this issue p. eabb4853 ; see also p. 1052
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- 2020
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4. La Dolce Vita of Neurexin: Synaptic Partnerships through Glycosaminoglycans
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Michisuke Yuzaki and Kunimichi Suzuki
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0301 basic medicine ,Neurexin ,synaptic adhesion protein ,Nerve Tissue Proteins ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Glycosaminoglycan ,03 medical and health sciences ,chemistry.chemical_compound ,neurexin ,heparan sulphate ,mossy fiber ,synaptic transmission ,Glycosaminoglycans ,LRRTM ,Neurons ,synaptogenesis ,proteoglycan ,integumentary system ,fungi ,Heparan sulfate ,Cell biology ,Synaptic function ,030104 developmental biology ,chemistry ,Synapses ,Heparitin Sulfate ,neuroligin ,thorny excrescence - Abstract
Summary Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared genetic risk pathway in autism and schizophrenia. Neurexin’s role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses. HS directly binds postsynaptic partners neuroligins and LRRTMs, revealing a dual binding mode involving intrinsic glycan and protein domains for canonical synapse-organizing complexes. Neurexin HS chains also bind novel ligands, potentially expanding the neurexin interactome to hundreds of HS-binding proteins. Because HS structure is heterogeneous, our findings indicate an additional dimension to neurexin diversity, provide a molecular basis for fine-tuning synaptic function, and open therapeutic directions targeting glycan-binding motifs critical for brain development., Graphical Abstract, Highlights • Brain central synaptic organizers neurexins are heparan sulfate (HS) proteoglycans • A dual HS and protein domain mode mediates neurexin binding to neuroligin and LRRTM • HS increases neurexin heterogeneity and expands its interactome to HS binding factors • HS glycan on neurexin is required for normal synaptic development and mouse survival, Neurexins, major synaptic-organizing proteins, are heparan sulfate (HS) proteoglycans, and HS modification is required for neurexin functions in synaptic transmission, development, and behavior.
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- 2018
5. Memantine reduces the production of amyloid-β peptides through modulation of amyloid precursor protein trafficking
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Kaori Ito, Maki Hayakawa, Hideo Kubo, Kunimichi Suzuki, Takashi Hirayama, Taisuke Tomita, Mitsuhiro Makino, and Takuya Tatebe
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0301 basic medicine ,Genetically modified mouse ,medicine.drug_class ,Cell ,Pharmacology ,Receptors, N-Methyl-D-Aspartate ,03 medical and health sciences ,Glutamatergic ,Mice ,0302 clinical medicine ,Memantine ,medicine ,Amyloid precursor protein ,Animals ,Aspartic Acid Endopeptidases ,Neurons ,Amyloid beta-Peptides ,biology ,Chemistry ,Brain ,Receptor antagonist ,Endocytosis ,Peptide Fragments ,Rats ,Protein Transport ,030104 developmental biology ,medicine.anatomical_structure ,Solubility ,biology.protein ,NMDA receptor ,Amyloid Precursor Protein Secretases ,030217 neurology & neurosurgery ,Intracellular ,medicine.drug - Abstract
Memantine, an uncompetitive glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used as medication for the treatment of Alzheimer's disease (AD). It has been reported that memantine reduces amyloid-β peptide (Aβ) levels in both neuronal cultures and in brains of animal models of AD. However, the underlying mechanism of these effects is unclear. Here we examined the effect of memantine on Aβ production. Memantine was administered to 9-month-old Tg2576 mice, a transgenic mouse model of AD, at 10 or 20mg/kg/day in drinking water for 1 month. Memantine significantly reduced the amounts of both CHAPS-soluble and CHAPS-insoluble Aβ in the brains of Tg2576 mice. Memantine at 10mg/kg/day for 1 month also reduced the levels of insoluble Aβ42 in the brains of aged F344 rats. Moreover, memantine reduced Aβ and sAPPβ levels in conditioned media from rat primary cortical cultures without affecting the enzymatic activities of α-secretase, β-secretase, or γ-secretase. Notably, in a cell-surface biotinylation assay, memantine increased the amount of amyloid precursor protein (APP) at the cell surface without changing the total amount of APP. Collectively, our results indicate that chronic treatment with memantine reduces the levels of Aβ both in AD models and in aged animals, and that memantine affects the endocytosis pathway of APP, which is required for β-secretase-mediated cleavage. This leads to a reduction in Aβ production. These results suggest that memantine reduces Aβ production and plaque deposition through the regulation of intracellular trafficking of APP.
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- 2016
6. BACE1 Activity Is Modulated by Cell-Associated Sphingosine-1-Phosphate
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Taisuke Tomita, John Q. Trojanowski, Kunimichi Suzuki, Naoaki Shimada, Takuya Higo, Virginia M.-Y. Lee, Yukiko Hori, Tohru Fukuyama, Tomoki Sasaki, Satoshi Yokoshima, Takeshi Iwatsubo, Nobumasa Takasugi, Satoko Osawa, and Hayato Isshiki
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Sphingosine kinase ,Article ,Mice ,chemistry.chemical_compound ,Downregulation and upregulation ,Alzheimer Disease ,Sphingosine ,mental disorders ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Sphingosine-1-phosphate ,Cells, Cultured ,Cerebral Cortex ,Neurons ,Gene knockdown ,Amyloid beta-Peptides ,biology ,General Neuroscience ,SPHK2 ,chemistry ,Biochemistry ,biology.protein ,Phosphorylation ,RNA Interference ,lipids (amino acids, peptides, and proteins) ,Amyloid Precursor Protein Secretases ,Lysophospholipids ,Amyloid precursor protein secretase - Abstract
Sphingosine kinase (SphK) 1 and 2 phosphorylate sphingosine to generate sphingosine-1-phosphate (S1P), a pluripotent lipophilic mediator implicated in a variety of cellular events. Here we show that the activity of β-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for amyloid-β peptide (Aβ) production, is modulated by S1P in mouse neurons. Treatment by SphK inhibitor, RNA interference knockdown of SphK, or overexpression of S1P degrading enzymes decreased BACE1 activity, which reduced Aβ production. S1P specifically bound to full-length BACE1 and increased its proteolytic activity, suggesting that cellular S1P directly modulates BACE1 activity. Notably, the relative activity of SphK2 was upregulated in the brains of patients with Alzheimer's disease. The unique modulatory effect of cellular S1P on BACE1 activity is a novel potential therapeutic target for Alzheimer's disease.
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- 2011
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7. O1–08–06: Pathophysiological role of proteolytic cleavage of neuroligins
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Satoko Osawa, Taisuke Tomita, Kunimichi Suzuki, Takeshi Iwatsubo, and Azusa Shiohara
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Chemistry ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology ,Cleavage (embryo) ,Cell biology - Published
- 2013
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8. P3‐348: Neuron‐specific regulation of beta‐secretase activity by sphingosine kinase
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Kunimichi Suzuki, Nobumasa Takasugi, Hayato Isshiki, Taisuke Tomita, and Takeshi Iwatsubo
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PLCD3 ,MAP kinase kinase kinase ,biology ,Epidemiology ,Chemistry ,Health Policy ,Sphingosine kinase ,Lipid signaling ,Mitogen-activated protein kinase kinase ,Cell biology ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,medicine.anatomical_structure ,Developmental Neuroscience ,biology.protein ,medicine ,Neurology (clinical) ,Neuron ,Geriatrics and Gerontology ,Beta (finance) ,Amyloid precursor protein secretase - Published
- 2008
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9. Activity-Dependent Proteolytic Cleavage of Neuroligin-1
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Yukari Hayashi, Shun Tanimura, Paul Saftig, Norio Matsuki, Kunimichi Suzuki, Satoshi Yokoshima, Soichiro Nakahara, Tohru Fukuyama, Taisuke Tomita, Atsuko Sehara-Fujisawa, Ryuta Koyama, Hiroshi Kumazaki, Satoko Osawa, Mingshuo Zeng, Johannes Prox, Takeshi Iwatsubo, Yoshitake Nishiyama, and Keisuke Horiuchi
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Dendritic spine ,Ectodomain ,Biochemistry ,Postsynaptic potential ,General Neuroscience ,ADAM10 ,Neuroscience(all) ,Excitatory postsynaptic potential ,Neurexin ,Neuroligin ,Biology ,Presenilin ,Cell biology - Abstract
SummaryNeuroligin (NLG), a postsynaptic adhesion molecule, is involved in the formation of synapses by binding to a cognate presynaptic ligand, neurexin. Here we report that neuroligin-1 (NLG1) undergoes ectodomain shedding at the juxtamembrane stalk region to generate a secreted form of NLG1 and a membrane-tethered C-terminal fragment (CTF) in adult rat brains in vivo as well as in neuronal cultures. Pharmacological and genetic studies identified ADAM10 as the major protease responsible for NLG1 shedding, the latter being augmented by synaptic NMDA receptor activation or interaction with soluble neurexin ligands. NLG1-CTF was subsequently cleaved by presenilin/γ-secretase. Secretion of soluble NLG1 was significantly upregulated under a prolonged epileptic seizure condition, and inhibition of NLG1 shedding led to an increase in numbers of dendritic spines in neuronal cultures. Collectively, neuronal activity-dependent proteolytic processing of NLG1 may negatively regulate the remodeling of spines at excitatory synapses.
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