The Experts below are selected from a list of 585 Experts worldwide ranked by ideXlab platform
Yuji Ikegaya - One of the best experts on this subject based on the ideXlab platform.
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Mossy fiber Zn 2 � spillover modulates heterosynaptic N-methyl-D-aspartate receptor activity in hippocampal CA3 circuits
2013Co-Authors: Sayaka Ueno, Masako Tsukamoto, Tomoya Hirano, Kazuya Kikuchi, Maki K Yamada, Nobuyoshi Nishiyama, Tetsuo Nagano, Norio Matsuki, Yuji IkegayaAbstract:lthough Zn 2 � is contained in large amounts in the synaptic terminals of hippocampal mossy fibers (MFs), its physiological role in synaptic transmission is poorly understood. By using the newly developed high-sensitivity Zn2 � indicator ZnAF-2, the spatiotemporal dynamics of Zn2 � was monitored in rat hippocampal slices. When high-frequency stimulation was delivered to the MFs, the concentration of extracellular Zn2 � was immediately elevated in the Stratum Lucidum, followed by a mild increase in the Stratum radiatum adjacent to the Stratum Lucidum, but not in the distal area of Stratum radiatum. The Zn 2 � A increase was insensitive to a non– N-methyl-D-aspartate (NMDA) receptor antagonist but was efficiently attenuated by tetrodotoxin or Ca 2 �-free medium, suggesting that Zn 2 � is released by MF synaptic terminals in an activity-dependent manner, and thereafter diffuses extracellularly into the neighboring Stratum radiatum. Electrophysiological analyses revealed that NMDA receptor– mediated synaptic responses in CA3 proximal Stratum radiatum were inhibited in the immediate aftermath of MF activation and that this inhibition was no longer observed in the presence of a Zn 2 �-chelating agent. Thus, Zn 2 � serves as a spatiotemporal mediator in imprinting the history of MF activity in contiguous hippocampal networks. We predict herein a novel form of metaplasticity, i.e., an experiencedependent non-Hebbian modulation of synaptic plasticity
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Influence of brain-derived neurotrophic factor on pathfinding of dentate granule cell axons, the hippocampal mossy fibers
Molecular Brain, 2009Co-Authors: Makoto Tamura, Ryuta Koyama, Norio Matsuki, Yuji Ikegaya, Naohiro Tamura, Takamitsu Ikeda, Maki K YamadaAbstract:Mossy fibers, the dentate granule cell axons, are generated throughout an animal's lifetime. Mossy fiber paths and synapses are primarily restricted to the Stratum Lucidum within the CA3 region. Brain-derived neurotrophic factor (BDNF), a neurotrophin family protein that activates Trk neurotrophin receptors, is highly expressed in the Stratum Lucidum in an activity-dependent manner. The addition of a Trk neurotrophin receptor inhibitor, K252a, to cultured hippocampal slices induced aberrant extension of mossy fibers into ectopic regions. BDNF overexpression in granule cells ameliorated the mossy fiber pathway abnormalities caused by a submaximal dose of K252a. A similar rescue was observed when BDNF was expressed in CA3 pyramidal cells, most notably in mossy fibers distal to the expression site. These findings are the first to clarify the role of BDNF in mossy fiber pathfinding, not as an attractant cue but as a regulator, possibly acting in a paracrine manner. This effect of BDNF may be as a signal for new fibers to fasciculate and extend further to form synapses with neurons that are far from active BDNF-expressing synapses. This mechanism would ensure the emergence of new independent dentate gyrus-CA3 circuits by the axons of new-born granule cells.
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DEVELOPMENTAL NEUROSCIENCE NEUROREPORT K252a, an inhibitor of Trk, disturbs path¢nding
2005Co-Authors: Makoto Tamura, Ryuta Koyama, Norio Matsuki, Yuji Ikegaya, Maki K YamadaAbstract:Hippocampal mossy ¢bers, which are the axons of dentate granule cells, are continuously generated owing to adult neurogenesis of granule cells. They extend exclusively into the Stratum Lucidum, a proximal layer of the CA3 pyramidal cells.We visualized the mossy ¢ber tracts by Timm histochemical staining and DiI labeling in the cultured hippocampal slices from newborn rats. The ¢bers were abnormally expanded when the slices were cultured in the presence of K252a, an inhibitor of the neurotrophin receptorTrk. Similar defasciculation was observed with an inhibitor of MEK, which is one of the signaling molecules downstream of Trk. This study suggests for the ¢rst time that Trk and the MEK pathway are required for mossy ¢ber path¢nding. NeuroRepor
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Mossy Fiber Sprouting as a Potential Therapeutic Target for Epilepsy
Current Neurovascular Research, 2004Co-Authors: Ryuta Koyama, Yuji IkegayaAbstract:Hippocampal mossy fibers, axons of dentate granule cells, converge in the dentate hilus and run through a narrow area called the Stratum Lucidum to synapse with hilar and CA3 neurons. In the hippocampal formation of temporal lobe epilepsy patients, however, this stereotyped pattern of projection is often collapsed; the mossy fibers branch out of the dentate hilus and abnormally innervate the dentate inner molecular layer, a phenomenon that is termed mossy fiber sprouting. Experimental studies have replicated this sprouting in animal models of temporal lobe epilepsy, including kindling and pharmacological treatment with convulsants. Because these axon collaterals form recurrent excitatory inputs into dendrites of granule cells, the circuit reorganization is assumed to cause epileptiform activity in the hippocampus, whereas some recent studies indicate that the sprouting is not necessarily associated with early-life seizures. Here we review the mechanisms of mossy fiber sprouting and consider its potential contribution to epileptogenesis. Based on recent findings, we propose that the sprouting can be regarded as a result of disruption of the molecular mechanisms underlying the axon guidance. We finally focus on the possibility that prevention of the abnormal sprouting might be a new strategy for medical treatment with temporal lobe epilepsy.
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mossy fiber zn2 spillover modulates heterosynaptic n methyl d aspartate receptor activity in hippocampal ca3 circuits
Journal of Cell Biology, 2002Co-Authors: Sayaka Ueno, Masako Tsukamoto, Tomoya Hirano, Kazuya Kikuchi, Maki K Yamada, Nobuyoshi Nishiyama, Tetsuo Nagano, Norio Matsuki, Yuji IkegayaAbstract:Although Zn2+ is contained in large amounts in the synaptic terminals of hippocampal mossy fibers (MFs), its physiological role in synaptic transmission is poorly understood. By using the newly developed high-sensitivity Zn2+ indicator ZnAF-2, the spatiotemporal dynamics of Zn2+ was monitored in rat hippocampal slices. When high-frequency stimulation was delivered to the MFs, the concentration of extracellular Zn2+ was immediately elevated in the Stratum Lucidum, followed by a mild increase in the Stratum radiatum adjacent to the Stratum Lucidum, but not in the distal area of Stratum radiatum. The Zn2+ increase was insensitive to a non–N-methyl-d-aspartate (NMDA) receptor antagonist but was efficiently attenuated by tetrodotoxin or Ca2+-free medium, suggesting that Zn2+ is released by MF synaptic terminals in an activity-dependent manner, and thereafter diffuses extracellularly into the neighboring Stratum radiatum. Electrophysiological analyses revealed that NMDA receptor–mediated synaptic responses in CA3 proximal Stratum radiatum were inhibited in the immediate aftermath of MF activation and that this inhibition was no longer observed in the presence of a Zn2+-chelating agent. Thus, Zn2+ serves as a spatiotemporal mediator in imprinting the history of MF activity in contiguous hippocampal networks. We predict herein a novel form of metaplasticity, i.e., an experience-dependent non-Hebbian modulation of synaptic plasticity.
Takaomi C Saido - One of the best experts on this subject based on the ideXlab platform.
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region specific reduction of a beta degrading endopeptidase neprilysin in mouse hippocampus upon aging
Journal of Neuroscience Research, 2002Co-Authors: Nobuhisa Iwata, Yoshie Takaki, Shinjiro Fukami, Satoshi Tsubuki, Takaomi C SaidoAbstract:Metabolism of amyloid-β peptide (Aβ) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Neprilysin is the only rate-limiting catabolic peptidase proven by means of reverse genetics to participate in Aβ metabolism in vivo. The aim of the present study is to assess whether possible spatial changes in neprilysin level in the brain with aging correlate to AD-vulnerable regions. When neprilysin levels in various brain regions of 10-, 80- and 132-week-old mice were evaluated by neprilysin-dependent endopeptidase activity assay and Western blot-based quantitative analysis, a clear change in neprilysin level with aging was observed in the hippocampal formation, in which the level was reduced by 20% at 132 weeks, compared to the 10-week group. Quantitative immunohistochemical analysis confirmed a marked local reduction of neprilysin levels with aging at the outer molecular layer and polymorphic layer of the dentate gyrus, and the Stratum Lucidum of the hippocampus, where the densities were reduced by 56%, 82% and 83%, respectively, at 132 weeks compared to the 10-week group. Thus, neprilysin was decreased selectively at the terminal zones and on axons of the lateral perforant path and the mossy fibers. These are the sites that show Aβ pathology in mutant amyloid precursor protein (APP) transgenic mice, and that show synaptic loss in AD. The immunoreactivities to synaptic vesicle protein-2 and synaptophysin in the Stratum Lucidum and the dentate gyrus were unchanged, suggesting that a loss or decrease of synapses was not responsible for the decrease in the neprilysin levels. These observations suggest that downregulation of neprilysin is likely to be related to AD pathology and to the Aβ deposition associated with normal aging in humans. © 2002 Wiley-Liss, Inc.
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region specific reduction of a beta degrading endopeptidase neprilysin in mouse hippocampus upon aging
Journal of Neuroscience Research, 2002Co-Authors: Nobuhisa Iwata, Yoshie Takaki, Shinjiro Fukami, Satoshi Tsubuki, Takaomi C SaidoAbstract:Metabolism of amyloid-beta peptide (A beta) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Neprilysin is the only rate-limiting catabolic peptidase proven by means of reverse genetics to participate in A beta metabolism in vivo. The aim of the present study is to assess whether possible spatial changes in neprilysin level in the brain with aging correlate to AD-vulnerable regions. When neprilysin levels in various brain regions of 10-, 80- and 132-week-old mice were evaluated by neprilysin-dependent endopeptidase activity assay and Western blot-based quantitative analysis, a clear change in neprilysin level with aging was observed in the hippocampal formation, in which the level was reduced by 20% at 132 weeks, compared to the 10-week group. Quantitative immunohistochemical analysis confirmed a marked local reduction of neprilysin levels with aging at the outer molecular layer and polymorphic layer of the dentate gyrus, and the Stratum Lucidum of the hippocampus, where the densities were reduced by 56%, 82% and 83%, respectively, at 132 weeks compared to the 10-week group. Thus, neprilysin was decreased selectively at the terminal zones and on axons of the lateral perforant path and the mossy fibers. These are the sites that show A beta pathology in mutant amyloid precursor protein (APP) transgenic mice, and that show synaptic loss in AD. The immunoreactivities to synaptic vesicle protein-2 and synaptophysin in the Stratum Lucidum and the dentate gyrus were unchanged, suggesting that a loss or decrease of synapses was not responsible for the decrease in the neprilysin levels. These observations suggest that downregulation of neprilysin is likely to be related to AD pathology and to the A beta deposition associated with normal aging in humans.
Shinjiro Fukami - One of the best experts on this subject based on the ideXlab platform.
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region specific reduction of a beta degrading endopeptidase neprilysin in mouse hippocampus upon aging
Journal of Neuroscience Research, 2002Co-Authors: Nobuhisa Iwata, Yoshie Takaki, Shinjiro Fukami, Satoshi Tsubuki, Takaomi C SaidoAbstract:Metabolism of amyloid-β peptide (Aβ) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Neprilysin is the only rate-limiting catabolic peptidase proven by means of reverse genetics to participate in Aβ metabolism in vivo. The aim of the present study is to assess whether possible spatial changes in neprilysin level in the brain with aging correlate to AD-vulnerable regions. When neprilysin levels in various brain regions of 10-, 80- and 132-week-old mice were evaluated by neprilysin-dependent endopeptidase activity assay and Western blot-based quantitative analysis, a clear change in neprilysin level with aging was observed in the hippocampal formation, in which the level was reduced by 20% at 132 weeks, compared to the 10-week group. Quantitative immunohistochemical analysis confirmed a marked local reduction of neprilysin levels with aging at the outer molecular layer and polymorphic layer of the dentate gyrus, and the Stratum Lucidum of the hippocampus, where the densities were reduced by 56%, 82% and 83%, respectively, at 132 weeks compared to the 10-week group. Thus, neprilysin was decreased selectively at the terminal zones and on axons of the lateral perforant path and the mossy fibers. These are the sites that show Aβ pathology in mutant amyloid precursor protein (APP) transgenic mice, and that show synaptic loss in AD. The immunoreactivities to synaptic vesicle protein-2 and synaptophysin in the Stratum Lucidum and the dentate gyrus were unchanged, suggesting that a loss or decrease of synapses was not responsible for the decrease in the neprilysin levels. These observations suggest that downregulation of neprilysin is likely to be related to AD pathology and to the Aβ deposition associated with normal aging in humans. © 2002 Wiley-Liss, Inc.
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region specific reduction of a beta degrading endopeptidase neprilysin in mouse hippocampus upon aging
Journal of Neuroscience Research, 2002Co-Authors: Nobuhisa Iwata, Yoshie Takaki, Shinjiro Fukami, Satoshi Tsubuki, Takaomi C SaidoAbstract:Metabolism of amyloid-beta peptide (A beta) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Neprilysin is the only rate-limiting catabolic peptidase proven by means of reverse genetics to participate in A beta metabolism in vivo. The aim of the present study is to assess whether possible spatial changes in neprilysin level in the brain with aging correlate to AD-vulnerable regions. When neprilysin levels in various brain regions of 10-, 80- and 132-week-old mice were evaluated by neprilysin-dependent endopeptidase activity assay and Western blot-based quantitative analysis, a clear change in neprilysin level with aging was observed in the hippocampal formation, in which the level was reduced by 20% at 132 weeks, compared to the 10-week group. Quantitative immunohistochemical analysis confirmed a marked local reduction of neprilysin levels with aging at the outer molecular layer and polymorphic layer of the dentate gyrus, and the Stratum Lucidum of the hippocampus, where the densities were reduced by 56%, 82% and 83%, respectively, at 132 weeks compared to the 10-week group. Thus, neprilysin was decreased selectively at the terminal zones and on axons of the lateral perforant path and the mossy fibers. These are the sites that show A beta pathology in mutant amyloid precursor protein (APP) transgenic mice, and that show synaptic loss in AD. The immunoreactivities to synaptic vesicle protein-2 and synaptophysin in the Stratum Lucidum and the dentate gyrus were unchanged, suggesting that a loss or decrease of synapses was not responsible for the decrease in the neprilysin levels. These observations suggest that downregulation of neprilysin is likely to be related to AD pathology and to the A beta deposition associated with normal aging in humans.
Dimitri M. Kullmann - One of the best experts on this subject based on the ideXlab platform.
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Development/Plasticity/Repair Plasticity of GABA B Receptor-Mediated Heterosynaptic Interactions at Mossy Fibers After Status Epilepticus
2013Co-Authors: Ra P. Princivalle, Ruth Fabian-fine, Norman G. Bowery, Dimitri M. Kullmann, Matthew C. WalkerAbstract:Several neurotransmitters, including GABA acting at presynaptic GABAB receptors, modulate glutamate release at synapses between hippocampal mossy fibers and CA3 pyramidal neurons. This phenomenon gates excitation of the hippocampus and may therefore prevent limbic seizure propagation. Here we report that status epilepticus, triggered by either perforant path stimulation or pilocarpine administration, was followed 24 hr later by a loss of GABAB receptor-mediated heterosynaptic depression among populations of mossy fibers. This was accompanied by a decrease in the sensitivity of mossy fiber transmission to the exogenous GABAB receptor agonist baclofen. Autoradiography revealed a reduction in GABAB receptor binding in the Stratum Lucidum after status epilepticus. Failure of GABAB receptor-mediated modulation of mossy fiber transmission at mossy fibers may contribute to the development of spontaneous seizures after status epilepticus. Key words: epilepsy; GABAB receptor; status epilepticus; mossy fibers; CA3; seizure
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Ionotropic receptors at hippocampal mossy fibers: roles in axonal excitability, synaptic transmission, and plasticity
Frontiers in neural circuits, 2013Co-Authors: Arnaud Ruiz, Dimitri M. KullmannAbstract:Dentate granule cells process information from the enthorinal cortex en route to the hippocampus proper. These neurons have a very negative resting membrane potential and are relatively silent in the slice preparation. They are also subject to strong feed-forward inhibition. Their unmyelinated axon or mossy fibre ramifies extensively in the hilus and projects to Stratum Lucidum where it makes giant en-passant boutons with CA3 pyramidal neurons. There is compelling evidence that mossy fibre boutons express presynaptic GABAA receptors, which are commonly found in granule cell dendrites. There is also suggestive evidence for the presence of other ionotropic receptors, including glycine, NMDA and kainate receptors, in mossy fibre boutons. These presynaptic receptors have been proposed to lead to mossy fibre membrane depolarisation. How this phenomenon alters the excitability of synaptic boutons, the shape of presynaptic action potentials, Ca2+ influx and neurotransmitter release has remained elusive, but high-resolution live imaging of individual varicosities and direct patch-clamp recordings have begun to shed light on these phenomena. Presynaptic GABAA and kainate receptors have also been reported to facilitate the induction of long-term potentiation at mossy fibre – CA3 synapses. Although mossy fibres are highly specialised, some of the principles emerging at this connection may apply elsewhere in the CNS.
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Plasticity of GABAB Receptor-Mediated Heterosynaptic Interactions at Mossy Fibers After Status Epilepticus
The Journal of Neuroscience, 2003Co-Authors: Kate Chandler, Alessandra P. Princivalle, Ruth Fabian-fine, Norman G. Bowery, Dimitri M. Kullmann, Matthew C. WalkerAbstract:Several neurotransmitters, including GABA acting at presynaptic GABAB receptors, modulate glutamate release at synapses between hippocampal mossy fibers and CA3 pyramidal neurons. This phenomenon gates excitation of the hippocampus and may therefore prevent limbic seizure propagation. Here we report that status epilepticus, triggered by either perforant path stimulation or pilocarpine administration, was followed 24 hr later by a loss of GABAB receptor-mediated heterosynaptic depression among populations of mossy fibers. This was accompanied by a decrease in the sensitivity of mossy fiber transmission to the exogenous GABAB receptor agonist baclofen. Autoradiography revealed a reduction in GABAB receptor binding in the Stratum Lucidum after status epilepticus. Failure of GABAB receptor-mediated modulation of mossy fiber transmission at mossy fibers may contribute to the development of spontaneous seizures after status epilepticus.
Nobuhisa Iwata - One of the best experts on this subject based on the ideXlab platform.
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region specific reduction of a beta degrading endopeptidase neprilysin in mouse hippocampus upon aging
Journal of Neuroscience Research, 2002Co-Authors: Nobuhisa Iwata, Yoshie Takaki, Shinjiro Fukami, Satoshi Tsubuki, Takaomi C SaidoAbstract:Metabolism of amyloid-β peptide (Aβ) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Neprilysin is the only rate-limiting catabolic peptidase proven by means of reverse genetics to participate in Aβ metabolism in vivo. The aim of the present study is to assess whether possible spatial changes in neprilysin level in the brain with aging correlate to AD-vulnerable regions. When neprilysin levels in various brain regions of 10-, 80- and 132-week-old mice were evaluated by neprilysin-dependent endopeptidase activity assay and Western blot-based quantitative analysis, a clear change in neprilysin level with aging was observed in the hippocampal formation, in which the level was reduced by 20% at 132 weeks, compared to the 10-week group. Quantitative immunohistochemical analysis confirmed a marked local reduction of neprilysin levels with aging at the outer molecular layer and polymorphic layer of the dentate gyrus, and the Stratum Lucidum of the hippocampus, where the densities were reduced by 56%, 82% and 83%, respectively, at 132 weeks compared to the 10-week group. Thus, neprilysin was decreased selectively at the terminal zones and on axons of the lateral perforant path and the mossy fibers. These are the sites that show Aβ pathology in mutant amyloid precursor protein (APP) transgenic mice, and that show synaptic loss in AD. The immunoreactivities to synaptic vesicle protein-2 and synaptophysin in the Stratum Lucidum and the dentate gyrus were unchanged, suggesting that a loss or decrease of synapses was not responsible for the decrease in the neprilysin levels. These observations suggest that downregulation of neprilysin is likely to be related to AD pathology and to the Aβ deposition associated with normal aging in humans. © 2002 Wiley-Liss, Inc.
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region specific reduction of a beta degrading endopeptidase neprilysin in mouse hippocampus upon aging
Journal of Neuroscience Research, 2002Co-Authors: Nobuhisa Iwata, Yoshie Takaki, Shinjiro Fukami, Satoshi Tsubuki, Takaomi C SaidoAbstract:Metabolism of amyloid-beta peptide (A beta) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Neprilysin is the only rate-limiting catabolic peptidase proven by means of reverse genetics to participate in A beta metabolism in vivo. The aim of the present study is to assess whether possible spatial changes in neprilysin level in the brain with aging correlate to AD-vulnerable regions. When neprilysin levels in various brain regions of 10-, 80- and 132-week-old mice were evaluated by neprilysin-dependent endopeptidase activity assay and Western blot-based quantitative analysis, a clear change in neprilysin level with aging was observed in the hippocampal formation, in which the level was reduced by 20% at 132 weeks, compared to the 10-week group. Quantitative immunohistochemical analysis confirmed a marked local reduction of neprilysin levels with aging at the outer molecular layer and polymorphic layer of the dentate gyrus, and the Stratum Lucidum of the hippocampus, where the densities were reduced by 56%, 82% and 83%, respectively, at 132 weeks compared to the 10-week group. Thus, neprilysin was decreased selectively at the terminal zones and on axons of the lateral perforant path and the mossy fibers. These are the sites that show A beta pathology in mutant amyloid precursor protein (APP) transgenic mice, and that show synaptic loss in AD. The immunoreactivities to synaptic vesicle protein-2 and synaptophysin in the Stratum Lucidum and the dentate gyrus were unchanged, suggesting that a loss or decrease of synapses was not responsible for the decrease in the neprilysin levels. These observations suggest that downregulation of neprilysin is likely to be related to AD pathology and to the A beta deposition associated with normal aging in humans.