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Sadao Shiosaka - One of the best experts on this subject based on the ideXlab platform.
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ablation of Neuropsin neuregulin 1 signaling imbalances erbb4 inhibitory networks and disrupts hippocampal gamma oscillation
Translational Psychiatry, 2017Co-Authors: M Kawata, Sadao Shiosaka, S Morikawa, Hideki TamuraAbstract:Parvalbumin-expressing interneurons are pivotal for the processing of information in healthy brain, whereas the coordination of these functions is seriously disrupted in diseased brain. How these interneurons in the hippocampus participate in pathological functions remains unclear. We previously reported that neuregulin 1 (NRG1)–ErbB4 signaling, which is actuated by Neuropsin, is important for coordinating brain plasticity. Neuropsin cleaves mature NRG1 (bound to extracellular glycosaminoglycans) in response to long-term potentiation or depression, liberating a soluble ligand that activates its receptor, ErbB4. Here, we show in mice that kainate-induced status epilepticus transiently elevates the proteolytic activity of Neuropsin and stimulates cFos expression with a time course suggesting that activation of ErbB4- and parvalbumin-expressing interneurons follows the excitation and subsequent silencing of pyramidal neurons. In Neuropsin-deficient mice, kainate administration impaired signaling and disrupted the neuronal excitation–inhibition balance (E/I balance) in hippocampal networks, by decreasing the activity of parvalbumin-positive interneurons while increasing that of pyramidal neurons, resulting in the progression of status epilepticus. Slow, but not fast, gamma oscillations in Neuropsin-deficient mice showed reduced power. Intracerebroventricular infusion of the soluble NRG1 ligand moiety restored the E/I balance, status epilepticus and gamma oscillations to normal levels. These results suggest that the Neuropsin–NRG1 signaling system has a role in pathological processes underlying temporal lobe epilepsy by regulating the activity of parvalbumin-expressing interneurons, and that Neuropsin regulates E/I balance and gamma oscillations through NRG1–ErbB4 signaling toward parvalbumin-expressing interneurons. This neuronal system may be a useful target of pharmacological therapies against cognitive disorders.
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Decidualization Induces the Expression and Activation of an Extracellular Protease Neuropsin in Mouse Uterus1
2016Co-Authors: Shigetaka Yoshida, Sadao ShiosakaAbstract:Uterine decidualization is accompanied by the remodeling of the cell-matrix and cell-cell interactions around the endometrial stromal cells to allow an appropriate invasion of trophoblasts. This remodeling is thought to require the proteolysis of extra-cellular matrix proteins or cell adhesion molecules; however, the molecular mechanism remains poorly understood. In this study, decidualization induced the expression and activation of an ex-tracellular serine protease Neuropsin in the mouse uterus. Al-though nonpregnant uteri contained little Neuropsin, the protein content and enzymatic activity increased markedly and peaked at the midgestational period in pregnant uteri. Neuropsin ex-pression and activity was also upregulated in artificially induced deciduomata but not in nondecidualized pseudopregnant uteri. Neuropsin is the first extracellular protease to show the evident induction of expression and activity by decidualization and might contribute to the remodeling of extracellular components after decidualization. decidua, gene regulation, pregnancy, uteru
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Role of Neuropsin in parvalbumin immunoreactivity changes in hippocampal basket terminals of mice reared in various environments.
Frontiers in cellular neuroscience, 2014Co-Authors: Harumitsu Suzuki, Yasuyuki Ishikawa, Dai Kanagawa, Hitomi Nakazawa, Yoshie Tawara-hirata, Yoko Kogure, Chigusa Shimizu-okabe, Chitoshi Takayama, Sadao ShiosakaAbstract:In vitro approaches have suggested that Neuropsin (or kallikrein 8/KLK8), which controls gamma-aminobutyric acid (GABA) neurotransmission through neuregulin-1 (NRG-1) and its receptor (ErbB4), is involved in neural plasticity (Tamura et al., 2012, 2013). In the present study, we examined whether parvalbumin (PV)-positive neuronal networks, the majority of which are ErbB4-positive GABAergic interneurons, are controlled by Neuropsin in tranquil and stimulated voluntarily behaving mice. Parvalbumin-immunoreactive fibers surrounding hippocampal pyramidal and granular neurons in mice reared in their home cage were decreased in Neuropsin-deficient mice, suggesting that Neuropsin controls PV immunoreactivity. One- or two-week exposures of wild mice to novel environments, in which they could behave freely and run voluntarily in a wheel resulted in a marked upregulation of both Neuropsin mRNA and protein in the hippocampus. To elucidate the functional relevance of the increase in Neuropsin during exposure to a rich environment, the intensities of PV-immunoreactive fibers were compared between Neuropsin-deficient and wild-type (WT) mice under environmental stimuli. When mice were transferred into novel cages (large cages with toys), the intensity of PV-immunoreactive fibers increased in WT mice and Neuropsin-deficient mice. Therefore, behavioral stimuli control a Neuropsin-independent form of PV immunoreactivity. However, the Neuropsin-dependent part of the change in PV-immunoreactive fibers may occur in the stimulated hippocampus because increased levels of Neuropsin continued during these enriched conditions.
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Neuropsin-Dependent and -Independent Synaptic Tagging and Modulation of Long-Term Potentiation: A Quest for the Associated Signaling Pathway(s)
Synaptic Tagging and Capture, 2014Co-Authors: Yasuyuki Ishikawa, Sadao ShiosakaAbstract:Synaptic tagging is plausible hypothesis that can potentially explain relational memory. However, it has not yet been cleared why and how the tagged synapses can be distinguished from the other non-activated synapses. Early-phase long-term potentiation (E-LTP)-related signaling molecules and intracellular molecular trafficking for capturing these toward tagged synapses have been considered as essential for synaptic tagging apparatus. In this chapter, we will describe a new mechanism of synaptic tagging which shares the common set of E-LTP induction mechanisms as above; that is, the E-LTP-specific proteolysis by Neuropsin, an extracellular serine protease, is involved in Neuropsin-dependent form of synaptic tagging.
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An implantable micro imaging device for molecular imaging in a brain of freely-moving mouse
2014 IEEE International Symposium on Bioelectronics and Bioinformatics (IEEE ISBB 2014), 2014Co-Authors: Kiyotaka Sasagawa, Mayumi Motoyama, Toshihiko Noda, Yasumi Ohta, Takashi Tokuda, Jun Ohta, Sadao ShiosakaAbstract:We have developed an implantable micro imaging device that can observe specific molecules such as Neuropsin in the deep brain of a freely-moving mouse with minimal invasiveness. A chemical substance, 4-methylcoumaryl-7-amide (MCA), which reacts with Neuropsin and changes to fluorophore, 7-amino-4-methyl coumarin (AMC), is injected by a specially designed cannula employed with the device. The implanted sensor can measure spatio-temporal dynamics of neuropisn through fluorescence of AMC, which is accompanied by specific behavior in artificially induced epilepsy. The damage induced by the implantation of the device has been investigated. Four weeks after the implantation, no connective tissues are observed at the implanted locations and imaging was successfully conducted. Immuno-staining of the brain after the implantation reveals that the damage area is limited in less than 100 μm from the sensor surface.
Shigetaka Yoshida - One of the best experts on this subject based on the ideXlab platform.
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Decidualization Induces the Expression and Activation of an Extracellular Protease Neuropsin in Mouse Uterus1
2016Co-Authors: Shigetaka Yoshida, Sadao ShiosakaAbstract:Uterine decidualization is accompanied by the remodeling of the cell-matrix and cell-cell interactions around the endometrial stromal cells to allow an appropriate invasion of trophoblasts. This remodeling is thought to require the proteolysis of extra-cellular matrix proteins or cell adhesion molecules; however, the molecular mechanism remains poorly understood. In this study, decidualization induced the expression and activation of an ex-tracellular serine protease Neuropsin in the mouse uterus. Al-though nonpregnant uteri contained little Neuropsin, the protein content and enzymatic activity increased markedly and peaked at the midgestational period in pregnant uteri. Neuropsin ex-pression and activity was also upregulated in artificially induced deciduomata but not in nondecidualized pseudopregnant uteri. Neuropsin is the first extracellular protease to show the evident induction of expression and activity by decidualization and might contribute to the remodeling of extracellular components after decidualization. decidua, gene regulation, pregnancy, uteru
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Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury.
Neuroscience, 2007Co-Authors: Ryuji Terayama, Yoshio Bando, K. Murakami, K. Kato, Mari Kishibe, Shigetaka YoshidaAbstract:Abstract Previous studies indicated that the expression of Neuropsin, a serine protease, is induced in mature oligodendrocytes after injury to the CNS. The pathophysiology of spinal cord injury (SCI) involves primary and secondary mechanisms, the latter contributing further to permanent losses of function. To explore the role of Neuropsin after SCI, histochemical and behavioral analyses were performed in wild-type (WT) and Neuropsin-deficient (Neuropsin−/−) mice using a crush injury model, a well-characterized and consistently reproducible model of SCI. In situ hybridization revealed that Neuropsin mRNA expression was induced in the spinal cord white matter from WT mice after crush SCI, peaking at day 4. Neuropsin−/− mice showed attenuated demyelination, oligodendrocyte death, and axonal damage after SCI. Although axonal degeneration in the corticospinal tract was obvious caudal to the lesion site in both strains of mice after SCI, the number of surviving nerve fibers caudal to the lesion was significantly larger in Neuropsin−/− mice than WT mice. Behavioral analysis revealed that the recovery at days 10–42 was significantly improved in Neuropsin−/− mice compared with WT mice in spite of the severe initial hindlimb impairments due to SCI in both strains. These observations suggest that Neuropsin is involved in the secondary phase of the pathogenesis of SCI mediated by demyelination, oligodendrocyte death, and axonal degeneration.
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Involvement of Neuropsin in the pathogenesis of experimental autoimmune encephalomyelitis
Glia, 2005Co-Authors: Ryuji Terayama, Yoshio Bando, Masahiro Yamada, Shigetaka YoshidaAbstract:Inflammation, demyelination, and axonal damage of the central nervous system (CNS) are major pathological features of multiple sclerosis (MS). Proteolytic digestion of the blood-brain barrier and myelin protein by serine proteases is known to contribute to the development and progression of MS. Neuropsin, a serine protease, has a role in neuronal plasticity, and its expression has been shown to be upregulated in response to injury to the CNS. To determine the possible involvement of Neuropsin in demyelinating diseases of the CNS, we examined its expression in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a recognized animal model for MS. Neuropsin mRNA expression was induced in the spinal cord white matter of mice with EAE. Combined in situ hybridization and immunohistochemistry demonstrated that most of the cells expressing Neuropsin mRNA showed immunoreactivity for CNPase, a cell-specific marker for oligodendrocytes. Mice lacking Neuropsin (Neuropsin−/−) exhibited an altered EAE progression characterized by delayed onset and progression of clinical symptoms as compared to wild-type mice. Neuropsin−/− mice also showed attenuated demyelination and delayed oligodendroglial death early during the course of EAE. These observations suggest that Neuropsin is involved in the pathogenesis of EAE mediated by demyelination and oligodendroglial death. © 2005 Wiley-Liss, Inc.
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Differential expression of Neuropsin and protease M/neurosin in oligodendrocytes after injury to the spinal cord.
Glia, 2004Co-Authors: Ryuji Terayama, Yoshio Bando, Takayuki Takahashi, Shigetaka YoshidaAbstract:Neuropsin and protease M/neurosin are serine proteases expressed by neurons and glial cells, and serve a variety of functions in the central nervous system (CNS). The current study demonstrates changes in the expression of these proteases following hemisection of the mouse spinal cord. Within unlesioned spinal cord, Neuropsin mRNA expression was occasionally observed in the gray but not white matter, while the level of protease M/neurosin mRNA was higher in the white matter. After injury to the spinal cord, Neuropsin mRNA expression was induced in the white matter in the area immediately adjacent to the lesion, peaking at 4 days post-injury and disappearing by 14 days. Enhanced expression of protease M/neurosin mRNA was observed throughout the white and gray matter surrounding the lesion, peaking at 4 days and persisting for 14 days. Neuropsin mRNA was expressed predominantly by CNPase-positive oligodendrocytes. Furthermore, most of these cells were also associated with immunoreactivity for protease M/neurosin protein. Within unlesioned spinal cord, most protease M/neurosin mRNA-expressing cells were CNPase-positive oligodendrocytes, and a substantial fraction of these cells also showed immunoreactivity for NG2, a marker for oligodendrocyte progenitors. After injury, protease M/neurosin mRNA expression within NG2-positive cells was significantly decreased, while the constitutive expression in CNPase-positive oligodendrocytes appeared to be preserved. These findings suggest that each subpopulation of oligodendrocytes based on the expression of Neuropsin and protease M/neurosin has different roles in the response of the spinal cord to injury as well as in normal homeostasis.
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prolonged recovery of ultraviolet b irradiated skin in Neuropsin klk8 deficient mice
British Journal of Dermatology, 2003Co-Authors: T. Kirihara, Yukiko Nakamura, Shigetaka Yoshida, T. Sadayama, Kazumasa Matsumotomiyai, Sadao ShiosakaAbstract:Summary Background Neuropsin (KLK8), a serine protease of the kallikrein family, is thought to be involved in the function of keratinocytes, i.e. migration, differentiation and desquamation. However, how Neuropsin participates is still unknown. Objective To observe the epidermal function of serine protease in Neuropsin-deficient mice. Methods We irradiated the skin of Neuropsin-deficient mice with ultraviolet light to induce acute inflammation and compared the morphology with that of wild-type mice. Results We observed a phenotypic change in the epidermis. An acute inflammatory dose of ultraviolet light induced a marked increase in Neuropsin mRNA expression in the skin. The signal intensity of the mRNA expression was highest on day 2–3 after irradiation, when keratinocytes were aligned irregularly in the recovery period. Morphological comparison between Neuropsin –/– and +/+ mice revealed that an irregular alignment of cells in the thickened epidermis was obvious on day 2 after irradiation in the wild-type mice, whereas it was prolonged for at least 2 days in the Neuropsin-deficient mice. The stratum corneum of Neuropsin-deficient mice was remarkably thicker than that of the wild-type mice at 5, 14 and 21 days after irradiation. The increase, as a response to this stimulus, in involucrin immunoreactivity, a marker for cell envelope assembly, was delayed in the mutant mice. Conclusions Thus, Neuropsin might be involved early in the process of differentiation, such as in the assembly of the cell envelope, but not in migration and desquamation.
Keiko Kato - One of the best experts on this subject based on the ideXlab platform.
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Extracellular serine protease Neuropsin (KLK8) modulates neurite outgrowth and fasciculation of mouse hippocampal neurons in culture
Neuroscience letters, 2002Co-Authors: Takuya Oka, Sadao Shiosaka, Morito Akisada, Akihito Okabe, Katsutoshi Sakurai, Keiko KatoAbstract:A serine protease Neuropsin expressed in the hippocampus of adult brain has been implicated in synaptic plasticity. We report here that endogenous Neuropsin was localized extracellularly in neuronal cell bodies and their neurites in mouse hippocampal cultures. Furthermore, we found that, in cultured mouse hippocampal neurons, recombinant Neuropsin enhanced neurite projection from soma after 14 h of culture and neuronal aggregation with neurite fascicles at 48 h. This suggests that Neuropsin is involved in neurite outgrowth and fasciculation during the development of the nervous system.
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Role of loop structures of Neuropsin in the activity of serine protease and regulated secretion
The Journal of biological chemistry, 2002Co-Authors: Takuya Oka, Sadao Shiosaka, Toshio Hakoshima, Makoto Itakura, Saori Yamamori, Masami Takahashi, Yasuhide Hashimoto, Keiko KatoAbstract:Neuropsin involved in neural plasticity in adult mouse brain is a member of the S1 (clan SA) family of serine proteases and forms characteristic surface loops surrounding the substrate-binding site (Kishi, T., Kato, M., Shimizu, T., Kato, K., Matsumoto, K., Yoshida, S., Shiosaka, S., and Hakoshima, T. (1999)J. Biol. Chem. 274, 4220–4224). Little, however, is known about the roles of these loops. Thus, the present study investigated whether surface loop structures of Neuropsin were essential for the generation of enzymatic activity and/or secretion of the enzyme via a regulated secretory pathway. The loops include those stabilized by six disulfide bonds or a loop C (Gly69–Glu80) and anN-glycosylated kallikrein loop (His91–Ile103) not containing a site linked by a disulfide bond. First, among the six disulfide bonds, only SS1 in loop E (Gly142–Leu155) and SS6 in loop G (Ser185–Gly197) were necessary for the catalytic efficiency of Neuropsin. Second, disruptions of loop C and the N-linked oligosaccharide chain on the kallikrein loop affected the catalytic efficiency and P2 specificity, respectively. Alternatively, disruptions of loop C and the kallikrein loop enhanced the regulated secretion, whereas there was no one disruption that inhibited the secretion, indicating that there was no critical loop required for the regulated secretion among loops surrounding the substrate-binding site.
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Distribution of serine proteinase inhibitor, clade B, member 6 (Serpinb6) in the adult mouse brain.
Brain research. Gene expression patterns, 2002Co-Authors: Tadaaki Kishi, Hitomi Matsuhashi, Phillip I Bird, Keiko KatoAbstract:In the brain, Serpinb6 was identified as an endogenous inhibitor of Neuropsin, a member of the S1 (clan SA) family of serine proteases [J. Biol. Chem. 276 (2001) 14562]. In the present study, we investigated the localization of Serpinb6 in the adult mouse brain using in situ hybridization histochemistry and immunohistochemistry. Region-specific patterns of expression were observed and two characteristics were recognized. First, the forebrain limbic area that expressed Neuropsin mRNA contained Serpinb6 mRNA at moderate levels but not the lateral septum. On the other hand, Serpinb6 mRNA was also expressed moderately in the substantia nigra-ventral tegmental area system, whose fibers projected to the lateral septum. Additionally, Serpinb6 protein was detected in the lateral septum. Together, it was suggested that the expression of Neuropsin in the brain is regulated entirely by Serpinb6. Second, Serpinb6 mRNA and the protein were strongly expressed in most somatic and visceral motoneurons among cranial nerve nuclei. This suggests that another serine protease is regulated by Serpinb6 in motoneurons and/or fibers.
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D of serine proteinase inhibitor, clade B, member 6 (Serpinb6 ) in the adult mouse brain
2002Co-Authors: Tadaaki Kishi, Hitomi Matsuhashi, Phillip I Bird, Keiko KatoAbstract:In the brain, Serpinb6 was identified as an endogenous inhibitor of Neuropsin, a member of the S1 (clan SA) family of serine proteases [J. Biol. Chem. 276 (2001) 14562]. In the present study, we investigated the localization of Serpinb6 in the adult mouse brain using in situ hybridization histochemistry and immunohistochemistry. Region-specific patterns of expression were observed and two characteristics were recognized. First, the forebrain limbic area that expressed Neuropsin mRNA contained Serpinb6 mRNA at moderate levels but not the lateral septum. On the other hand, Serpinb6 mRNA was also expressed moderately in the substantia nigra–ventral tegmental area system, whose fibers projected to the lateral septum. Additionally, Serpinb6 protein was detected in the lateral septum. Together, it was suggested that the expression of Neuropsin in the brain is regulated entirely by Serpinb6. Second, Serpinb6 mRNA and the protein were strongly expressed in most somatic and visceral motoneurons among cranial nerve nuclei. This suggests that another serine protease is regulated by Serpinb6 in motoneurons and / or fibers. 2002 Elsevier Science B.V. All rights reserved. Theme: Cellular and molecular biology Topic: Staining, tracing, and imaging techniques
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Abnormalities of synapses and neurons in the hippocampus of Neuropsin-deficient mice.
Molecular and cellular neurosciences, 2001Co-Authors: Akio Hirata, Manabu Taniguchi, Tomohiro Matsuyama, Keiko Kato, Shigetaka Yoshida, Naoko Inoue, Kazumasa Matsumoto-miyai, Ayako Ninomiya, Hisashi Iizasa, Yuki KataokaAbstract:In the present study, we produced null-mutant mice of Neuropsin, an extracellular matrix serine protease, to examine the neural functions of this protein particularly in the hippocampus. Golgi-Cox impregnation and Nissl-staining revealed morphological change of cell soma in the mutant mice compared to wild-type mice. However, Golgi-Cox impregnation revealed no apparent change in the dendritic arborization and spine density. Quantitative electronmicroscopic analysis revealed that number of asymmetrical synapses were significantly decreased in the stratum radiatum, the major terminal field of Schaffer-collaterals, whereas free boutons still holding synaptic vesicles but with no synaptic specialization were increased in number in the same microscopic fields. An increased number of parvalbumin-immunoreactive cells (known as fast spiking cells) in mutant was also observed. These results strongly suggest that Neuropsin is involved in connectivity of a group of CA1 synapses and consequently in the hippocampal networking.
Hideki Tamura - One of the best experts on this subject based on the ideXlab platform.
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ablation of Neuropsin neuregulin 1 signaling imbalances erbb4 inhibitory networks and disrupts hippocampal gamma oscillation
Translational Psychiatry, 2017Co-Authors: M Kawata, Sadao Shiosaka, S Morikawa, Hideki TamuraAbstract:Parvalbumin-expressing interneurons are pivotal for the processing of information in healthy brain, whereas the coordination of these functions is seriously disrupted in diseased brain. How these interneurons in the hippocampus participate in pathological functions remains unclear. We previously reported that neuregulin 1 (NRG1)–ErbB4 signaling, which is actuated by Neuropsin, is important for coordinating brain plasticity. Neuropsin cleaves mature NRG1 (bound to extracellular glycosaminoglycans) in response to long-term potentiation or depression, liberating a soluble ligand that activates its receptor, ErbB4. Here, we show in mice that kainate-induced status epilepticus transiently elevates the proteolytic activity of Neuropsin and stimulates cFos expression with a time course suggesting that activation of ErbB4- and parvalbumin-expressing interneurons follows the excitation and subsequent silencing of pyramidal neurons. In Neuropsin-deficient mice, kainate administration impaired signaling and disrupted the neuronal excitation–inhibition balance (E/I balance) in hippocampal networks, by decreasing the activity of parvalbumin-positive interneurons while increasing that of pyramidal neurons, resulting in the progression of status epilepticus. Slow, but not fast, gamma oscillations in Neuropsin-deficient mice showed reduced power. Intracerebroventricular infusion of the soluble NRG1 ligand moiety restored the E/I balance, status epilepticus and gamma oscillations to normal levels. These results suggest that the Neuropsin–NRG1 signaling system has a role in pathological processes underlying temporal lobe epilepsy by regulating the activity of parvalbumin-expressing interneurons, and that Neuropsin regulates E/I balance and gamma oscillations through NRG1–ErbB4 signaling toward parvalbumin-expressing interneurons. This neuronal system may be a useful target of pharmacological therapies against cognitive disorders.
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Cellular/Molecular NMDA-Dependent Proteolysis of Presynaptic Adhesion Molecule L1 in the Hippocampus by Neuropsin
2013Co-Authors: Kazumasa Matsumoto-miyai, Hideki Tamura, Yukiko Nakamura, Ayako Ninomiya, Hironobu Yamasaki, Sadao ShiosakaAbstract:Synaptic plasticity requires an activity-dependent, rapid, and long-lasting modification of synaptic character, including morphology and coupling strength. Here we show that a serine protease, Neuropsin, directly and specifically modifies the synaptic adhesion molecule L1, which was localized to the presynaptic site of the asymmetric synapse in the mouse hippocampus. Increased neural activity triggered the rapid, transient activation of the precursor form of Neuropsin in an NMDA receptor-dependent manner. The activated Neuropsin immediately cleaved L1 and released a Neuropsin-specific extracellular 180 kDa fragment. This Neuropsin-specific L1-cleaving system is involved in NMDA receptor-dependent synaptic plasticity, such as the Schaffer collateral long-term potentiation
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Processing of neuregulin-1 by Neuropsin regulates GABAergic neuron to control neural plasticity of the mouse hippocampus.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012Co-Authors: Hideki Tamura, Yasuyuki Ishikawa, M Kawata, Seiya Hamaguchi, Sadao ShiosakaAbstract:Protease-mediated signaling is an important modulator of the nervous system. However, identifying the specific signaling substrates of such proteases is limited by the rapidity with which intermediate substrate forms are cleaved and released. Here, a screening method to detect noncleaved enzyme-bound forms was developed and used to identify a novel Neuropsin/neuregulin-1 (NRG-1) proteolytic signaling system, which is specifically localized in the microdomain of synaptic cleft, in the mouse hippocampus. The extracellular protease, Neuropsin, cleaved mature NRG-1 (comprising the extracellular domain of the NRG-1) at three newly identified sites to remove the heparin-binding domain of NRG-1. This released the ligand moiety from the matrix-glycosaminoglycan pool and enabled it to trigger the phosphorylation of NRG-1 receptor, p185 (ErbB4). Proteolysis of mature NRG-1 by Neuropsin led to colocalization of the processed NRG-1 with ErbB4 in parvalbumin-positive hippocampal interneurons and consequent phosphorylation of tyrosine residues of proteins in the cells. Moreover, Neuropsin knock-out mice exhibited impairments in Schaffer collateral early phase long-term potentiation, and application of the recombinant NRG-1 lacking heparin-binding activity reversed the effects through the activation of ErbB4 and GABA(A) receptors. Thus, ErbB4 signaling induced by Neuropsin-dependent processing of NRG-1 contributes to the modulation of synaptic plasticity via regulation of GABAergic transmission. This signaling system may be involved in human cognition and mental disorders, such as schizophrenia and bipolar disorder, by its dysfunction.
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Diversity of Neuropsin (KLK8)-dependent synaptic associativity in the hippocampal pyramidal neuron.
The Journal of Physiology, 2011Co-Authors: Yasuyuki Ishikawa, Hideki Tamura, Sadao ShiosakaAbstract:Non-technical summary Activity-dependent synaptic plasticity is widely accepted to provide a cellular basis for learning and memory. Synaptic associativity could be involved in activity-dependent synaptic plasticity, because it distinguishes between local mechanisms of synaptic tags and cell-wide mechanisms that are responsible for the synthesis of plasticity-related proteins. We report that a plasticity-related serine protease, Neuropsin, is involved in the tag-setting process during long-term potentiation (LTP) at basal and apical dendritic inputs. Neuropsin is involved in synaptic associativity during LTP at apical dendritic inputs via integrin β1 and CaMKII signalling. Thus, Neuropsin is a candidate molecule for LTP-specific tag-setting and could regulate the transformation of early to late LTP during synaptic associativity. These findings may provide the understanding of the regulation of synaptic associativity as complex information-processing systems. Abstract Hippocampal early (E-) long-term potentiation (LTP) and long-term depression (LTD) elicited by a weak stimulus normally fades within 90 min. Late (L-) LTP and LTD elicited by strong stimuli continue for >180 min and require new protein synthesis to persist. If a strong tetanus is applied once to synaptic inputs, even a weak tetanus applied to another synaptic input can evoke persistent LTP. A synaptic tag is hypothesized to enable the capture of newly synthesized synaptic molecules. This process, referred to as synaptic tagging, is found between not only the same processes (i.e. E- and L-LTP; E- and L-LTD) but also between different processes (i.e. E-LTP and L-LTD; E-LTD and L-LTP) induced at two independent synaptic inputs (cross-tagging). However, the mechanisms of synaptic tag setting remain unclear. In our previous study, we found that synaptic associativity in the hippocampal Schaffer collateral pathway depended on Neuropsin (kallikrein-related peptidase 8 or KLK8), a plasticity-related extracellular protease. In the present study, we investigated how Neuropsin participates in synaptic tagging and cross-tagging. We report that Neuropsin is involved in synaptic tagging during LTP at basal and apical dendritic inputs. Moreover, Neuropsin is involved in synaptic tagging and cross-tagging during LTP at apical dendritic inputs via integrin β1 and calcium/calmodulin-dependent protein kinase II signalling. Thus, Neuropsin is a candidate molecule for the LTP-specific tag setting and regulates the transformation of E- to L-LTP during both synaptic tagging and cross-tagging.
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Diversity of Neuropsin (KLK8)-dependent synaptic associativity in the hippocampal pyramidal neuron.
The Journal of physiology, 2011Co-Authors: Yasuyuki Ishikawa, Hideki Tamura, Sadao ShiosakaAbstract:Hippocampal early (E-) long-term potentiation (LTP) and long-term depression (LTD) elicited by a weak stimulus normally fades within 90 min. Late (L-) LTP and LTD elicited by strong stimuli continue for >180 min and require new protein synthesis to persist. If a strong tetanus is applied once to synaptic inputs, even a weak tetanus applied to another synaptic input can evoke persistent LTP. A synaptic tag is hypothesized to enable the capture of newly synthesized synaptic molecules. This process, referred to as synaptic tagging, is found between not only the same processes (i.e. E- and L-LTP; E- and L-LTD) but also between different processes (i.e. E-LTP and L-LTD; E-LTD and L-LTP) induced at two independent synaptic inputs (cross-tagging). However, the mechanisms of synaptic tag setting remain unclear. In our previous study, we found that synaptic associativity in the hippocampal Schaffer collateral pathway depended on Neuropsin (kallikrein-related peptidase 8 or KLK8), a plasticity-related extracellular protease. In the present study, we investigated how Neuropsin participates in synaptic tagging and cross-tagging. We report that Neuropsin is involved in synaptic tagging during LTP at basal and apical dendritic inputs. Moreover, Neuropsin is involved in synaptic tagging and cross-tagging during LTP at apical dendritic inputs via integrin β1 and calcium/calmodulin-dependent protein kinase II signalling. Thus, Neuropsin is a candidate molecule for the LTP-specific tag setting and regulates the transformation of E- to L-LTP during both synaptic tagging and cross-tagging.
Yasuyuki Ishikawa - One of the best experts on this subject based on the ideXlab platform.
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Role of Neuropsin in parvalbumin immunoreactivity changes in hippocampal basket terminals of mice reared in various environments.
Frontiers in cellular neuroscience, 2014Co-Authors: Harumitsu Suzuki, Yasuyuki Ishikawa, Dai Kanagawa, Hitomi Nakazawa, Yoshie Tawara-hirata, Yoko Kogure, Chigusa Shimizu-okabe, Chitoshi Takayama, Sadao ShiosakaAbstract:In vitro approaches have suggested that Neuropsin (or kallikrein 8/KLK8), which controls gamma-aminobutyric acid (GABA) neurotransmission through neuregulin-1 (NRG-1) and its receptor (ErbB4), is involved in neural plasticity (Tamura et al., 2012, 2013). In the present study, we examined whether parvalbumin (PV)-positive neuronal networks, the majority of which are ErbB4-positive GABAergic interneurons, are controlled by Neuropsin in tranquil and stimulated voluntarily behaving mice. Parvalbumin-immunoreactive fibers surrounding hippocampal pyramidal and granular neurons in mice reared in their home cage were decreased in Neuropsin-deficient mice, suggesting that Neuropsin controls PV immunoreactivity. One- or two-week exposures of wild mice to novel environments, in which they could behave freely and run voluntarily in a wheel resulted in a marked upregulation of both Neuropsin mRNA and protein in the hippocampus. To elucidate the functional relevance of the increase in Neuropsin during exposure to a rich environment, the intensities of PV-immunoreactive fibers were compared between Neuropsin-deficient and wild-type (WT) mice under environmental stimuli. When mice were transferred into novel cages (large cages with toys), the intensity of PV-immunoreactive fibers increased in WT mice and Neuropsin-deficient mice. Therefore, behavioral stimuli control a Neuropsin-independent form of PV immunoreactivity. However, the Neuropsin-dependent part of the change in PV-immunoreactive fibers may occur in the stimulated hippocampus because increased levels of Neuropsin continued during these enriched conditions.
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Neuropsin-Dependent and -Independent Synaptic Tagging and Modulation of Long-Term Potentiation: A Quest for the Associated Signaling Pathway(s)
Synaptic Tagging and Capture, 2014Co-Authors: Yasuyuki Ishikawa, Sadao ShiosakaAbstract:Synaptic tagging is plausible hypothesis that can potentially explain relational memory. However, it has not yet been cleared why and how the tagged synapses can be distinguished from the other non-activated synapses. Early-phase long-term potentiation (E-LTP)-related signaling molecules and intracellular molecular trafficking for capturing these toward tagged synapses have been considered as essential for synaptic tagging apparatus. In this chapter, we will describe a new mechanism of synaptic tagging which shares the common set of E-LTP induction mechanisms as above; that is, the E-LTP-specific proteolysis by Neuropsin, an extracellular serine protease, is involved in Neuropsin-dependent form of synaptic tagging.
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†Present address:
2014Co-Authors: Harumitsu Suzuki, Sadao Shiosaka, Yasuyuki Ishikawa, Dai Kanagawa, Hitomi Nakazawa, Yoshie Tawara-hirata, Yoko Kogure, Chitoshi Takayama, Ania K. MajewskaAbstract:doi: 10.3389/fncel.2014.00420 Role of Neuropsin in parvalbumin immunoreactivity changes in hippocampal basket terminals of mice reared i
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Processing of neuregulin-1 by Neuropsin regulates GABAergic neuron to control neural plasticity of the mouse hippocampus.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012Co-Authors: Hideki Tamura, Yasuyuki Ishikawa, M Kawata, Seiya Hamaguchi, Sadao ShiosakaAbstract:Protease-mediated signaling is an important modulator of the nervous system. However, identifying the specific signaling substrates of such proteases is limited by the rapidity with which intermediate substrate forms are cleaved and released. Here, a screening method to detect noncleaved enzyme-bound forms was developed and used to identify a novel Neuropsin/neuregulin-1 (NRG-1) proteolytic signaling system, which is specifically localized in the microdomain of synaptic cleft, in the mouse hippocampus. The extracellular protease, Neuropsin, cleaved mature NRG-1 (comprising the extracellular domain of the NRG-1) at three newly identified sites to remove the heparin-binding domain of NRG-1. This released the ligand moiety from the matrix-glycosaminoglycan pool and enabled it to trigger the phosphorylation of NRG-1 receptor, p185 (ErbB4). Proteolysis of mature NRG-1 by Neuropsin led to colocalization of the processed NRG-1 with ErbB4 in parvalbumin-positive hippocampal interneurons and consequent phosphorylation of tyrosine residues of proteins in the cells. Moreover, Neuropsin knock-out mice exhibited impairments in Schaffer collateral early phase long-term potentiation, and application of the recombinant NRG-1 lacking heparin-binding activity reversed the effects through the activation of ErbB4 and GABA(A) receptors. Thus, ErbB4 signaling induced by Neuropsin-dependent processing of NRG-1 contributes to the modulation of synaptic plasticity via regulation of GABAergic transmission. This signaling system may be involved in human cognition and mental disorders, such as schizophrenia and bipolar disorder, by its dysfunction.
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Diversity of Neuropsin (KLK8)-dependent synaptic associativity in the hippocampal pyramidal neuron.
The Journal of Physiology, 2011Co-Authors: Yasuyuki Ishikawa, Hideki Tamura, Sadao ShiosakaAbstract:Non-technical summary Activity-dependent synaptic plasticity is widely accepted to provide a cellular basis for learning and memory. Synaptic associativity could be involved in activity-dependent synaptic plasticity, because it distinguishes between local mechanisms of synaptic tags and cell-wide mechanisms that are responsible for the synthesis of plasticity-related proteins. We report that a plasticity-related serine protease, Neuropsin, is involved in the tag-setting process during long-term potentiation (LTP) at basal and apical dendritic inputs. Neuropsin is involved in synaptic associativity during LTP at apical dendritic inputs via integrin β1 and CaMKII signalling. Thus, Neuropsin is a candidate molecule for LTP-specific tag-setting and could regulate the transformation of early to late LTP during synaptic associativity. These findings may provide the understanding of the regulation of synaptic associativity as complex information-processing systems. Abstract Hippocampal early (E-) long-term potentiation (LTP) and long-term depression (LTD) elicited by a weak stimulus normally fades within 90 min. Late (L-) LTP and LTD elicited by strong stimuli continue for >180 min and require new protein synthesis to persist. If a strong tetanus is applied once to synaptic inputs, even a weak tetanus applied to another synaptic input can evoke persistent LTP. A synaptic tag is hypothesized to enable the capture of newly synthesized synaptic molecules. This process, referred to as synaptic tagging, is found between not only the same processes (i.e. E- and L-LTP; E- and L-LTD) but also between different processes (i.e. E-LTP and L-LTD; E-LTD and L-LTP) induced at two independent synaptic inputs (cross-tagging). However, the mechanisms of synaptic tag setting remain unclear. In our previous study, we found that synaptic associativity in the hippocampal Schaffer collateral pathway depended on Neuropsin (kallikrein-related peptidase 8 or KLK8), a plasticity-related extracellular protease. In the present study, we investigated how Neuropsin participates in synaptic tagging and cross-tagging. We report that Neuropsin is involved in synaptic tagging during LTP at basal and apical dendritic inputs. Moreover, Neuropsin is involved in synaptic tagging and cross-tagging during LTP at apical dendritic inputs via integrin β1 and calcium/calmodulin-dependent protein kinase II signalling. Thus, Neuropsin is a candidate molecule for the LTP-specific tag setting and regulates the transformation of E- to L-LTP during both synaptic tagging and cross-tagging.