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[PMID]:29343769
[Au] Autor:Chen X; Aslam M; Gollisch T; Allen K; von Engelhardt J
[Ad] Endereço:Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55128, Germany.
[Ti] Título:CKAMP44 modulates integration of visual inputs in the lateral geniculate nucleus.
[So] Source:Nat Commun;9(1):261, 2018 01 17.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Relay neurons in the dorsal lateral geniculate nucleus (dLGN) receive excitatory inputs from retinal ganglion cells (RGCs). Retinogeniculate synapses are characterized by a prominent short-term depression of AMPA receptor (AMPAR)-mediated currents, but the underlying mechanisms and its function for visual integration are not known. Here we identify CKAMP44 as a crucial auxiliary subunit of AMPARs in dLGN relay neurons, where it increases AMPAR-mediated current amplitudes and modulates gating of AMPARs. Importantly, CKAMP44 is responsible for the distinctive short-term depression in retinogeniculate synapses by reducing the rate of recovery from desensitization of AMPARs. Genetic deletion of CKAMP44 strongly reduces synaptic short-term depression, which leads to increased spike probability of relay neurons when activated with high-frequency inputs from retinogeniculate synapses. Finally, in vivo recordings reveal augmented ON- and OFF-responses of dLGN neurons in CKAMP44 knockout (CKAMP44 ) mice, demonstrating the importance of CKAMP44 for modulating synaptic short-term depression and visual input integration.
[Mh] Termos MeSH primário: Corpos Geniculados/fisiologia
Proteínas do Tecido Nervoso/metabolismo
Neurônios/fisiologia
Transmissão Sináptica/fisiologia
[Mh] Termos MeSH secundário: Animais
Eletrorretinografia
Potenciais Pós-Sinápticos Excitadores/fisiologia
Feminino
Corpos Geniculados/citologia
Corpos Geniculados/metabolismo
Camundongos Endogâmicos C57BL
Camundongos Knockout
Proteínas do Tecido Nervoso/genética
Neurônios/metabolismo
Estimulação Luminosa
Receptores de AMPA/metabolismo
Retina/citologia
Retina/metabolismo
Retina/fisiologia
Sinapses/fisiologia
Transmissão Sináptica/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CKAMP44 protein, mouse); 0 (Nerve Tissue Proteins); 0 (Receptors, AMPA)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180119
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02415-1


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[PMID]:29220673
[Au] Autor:Martin S; Chamberlin A; Shinde DN; Hempel M; Strom TM; Schreiber A; Johannsen J; Ousager LB; Larsen MJ; Hansen LK; Fatemi A; Cohen JS; Lemke J; Sørensen KP; Helbig KL; Lessel D; Abou Jamra R
[Ad] Endereço:Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany.
[Ti] Título:De Novo Variants in GRIA4 Lead to Intellectual Disability with or without Seizures and Gait Abnormalities.
[So] Source:Am J Hum Genet;101(6):1013-1020, 2017 Dec 07.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Using trio whole-exome sequencing, we have identified de novo heterozygous pathogenic variants in GRIA4 in five unrelated individuals with intellectual disability and other symptoms. GRIA4 encodes an AMPA receptor subunit known as GluR4, which is found on excitatory glutamatergic synapses and is important for learning and memory. Four of the variants are located in the highly conserved SYTANLAAF motif in the transmembrane protein M3, and the fifth is in an extra-cellular domain. Molecular modeling of the altered protein showed that three of the variants in the SYTANLAAF motif orient toward the center of the pore region and most likely lead to disturbance of the gating mechanism. The fourth variant in the SYTANLAAF motif most likely results in reduced permeability. The variant in the extracellular domain potentially interferes with the binding between the monomers. On the basis of clinical information and genetic results, and the fact that other subunits of the AMPA receptor have already been associated with neurodevelopmental disorders, we suggest that pathogenic de novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features.
[Mh] Termos MeSH primário: Transtornos Neurológicos da Marcha/genética
Deficiência Intelectual/genética
Transtornos dos Movimentos/genética
Receptores de AMPA/genética
Convulsões/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Pré-Escolar
Feminino
Seres Humanos
Masculino
Modelos Moleculares
Comportamento Problema
Comportamento Social
Sequenciamento Completo do Exoma
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, AMPA); 0 (glutamate receptor ionotropic, AMPA 4)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


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[PMID]:28461339
[Au] Autor:McGregor G; Irving AJ; Harvey J
[Ad] Endereço:Division of Neuroscience, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.
[Ti] Título:Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses.
[So] Source:FASEB J;31(8):3449-3466, 2017 08.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is involved in numerous cellular processes and it is implicated in neurodegenerative disorders, like Alzheimer disease. Recent studies identified a crucial role for this pathway in activity-dependent long-term depression (LTD) at hippocampal Schaffer collateral (SC)-CA1 synapses. However, it is unclear whether JAK-STAT signaling also regulates excitatory synaptic function at the anatomically distinct temporoammonic (TA) input to CA1 neurons. Here we demonstrate that LTD at adult TA-CA1 synapses involves JAK-STAT signaling, but unlike SC-CA1 synapses, requires rapid gene transcription. TA-CA1 LTD requires NMDA receptor activation and is independent of PI3K or ERK signaling. JAK-STAT signaling was critical for TA-CA1 LTD as inhibition of JAK or STAT blocked LTD induction and prevented NMDA-induced AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor internalization in hippocampal neurons. Moreover, an increase in phosphorylated JAK2 and STAT3 accompanied chemical induction of LTD and AMPA receptor internalization. STAT3-driven gene transcription was required for LTD as inhibition of STAT3-DNA binding, nuclear export, and gene transcription all prevented LTD induction. These data indicate an essential role for canonical JAK-STAT signaling in activity-dependent LTD at TA-CA1 synapses and provide valuable insight into the role of the TA input in hippocampal synaptic plasticity.-McGregor, G., Irving, A. J., Harvey, J. Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses.
[Mh] Termos MeSH primário: Região CA1 Hipocampal/fisiologia
Hipocampo/fisiologia
Janus Quinases/metabolismo
Fatores de Transcrição STAT/metabolismo
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Animais
Potenciais Pós-Sinápticos Excitadores/fisiologia
Regulação da Expressão Gênica/fisiologia
Janus Quinases/genética
Masculino
Plasticidade Neuronal/fisiologia
Neurônios/metabolismo
Transporte Proteico
Ratos
Ratos Sprague-Dawley
Receptores de AMPA/genética
Receptores de AMPA/metabolismo
Receptores de N-Metil-D-Aspartato/genética
Receptores de N-Metil-D-Aspartato/metabolismo
Fatores de Transcrição STAT/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, AMPA); 0 (Receptors, N-Methyl-D-Aspartate); 0 (STAT Transcription Factors); EC 2.7.10.2 (Janus Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601293RR


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[PMID]:29244810
[Au] Autor:Bliss DP; D'Esposito M
[Ad] Endereço:Helen Wills Neuroscience Institute, University of California, Berkeley, CA, United States of America.
[Ti] Título:Synaptic augmentation in a cortical circuit model reproduces serial dependence in visual working memory.
[So] Source:PLoS One;12(12):e0188927, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent work has established that visual working memory is subject to serial dependence: current information in memory blends with that from the recent past as a function of their similarity. This tuned temporal smoothing likely promotes the stability of memory in the face of noise and occlusion. Serial dependence accumulates over several seconds in memory and deteriorates with increased separation between trials. While this phenomenon has been extensively characterized in behavior, its neural mechanism is unknown. In the present study, we investigate the circuit-level origins of serial dependence in a biophysical model of cortex. We explore two distinct kinds of mechanisms: stable persistent activity during the memory delay period and dynamic "activity-silent" synaptic plasticity. We find that networks endowed with both strong reverberation to support persistent activity and dynamic synapses can closely reproduce behavioral serial dependence. Specifically, elevated activity drives synaptic augmentation, which biases activity on the subsequent trial, giving rise to a spatiotemporally tuned shift in the population response. Our hybrid neural model is a theoretical advance beyond abstract mathematical characterizations, offers testable hypotheses for physiological research, and demonstrates the power of biological insights to provide a quantitative explanation of human behavior.
[Mh] Termos MeSH primário: Córtex Cerebral/fisiologia
Memória de Curto Prazo/fisiologia
Modelos Neurológicos
Transmissão Sináptica/fisiologia
Vias Visuais/fisiologia
[Mh] Termos MeSH secundário: Córtex Cerebral/citologia
Simulação por Computador
Seres Humanos
Plasticidade Neuronal/fisiologia
Células Piramidais/citologia
Células Piramidais/fisiologia
Receptores de AMPA/fisiologia
Receptores de GABA-A/fisiologia
Receptores de N-Metil-D-Aspartato/fisiologia
Sinapses/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, AMPA); 0 (Receptors, GABA-A); 0 (Receptors, N-Methyl-D-Aspartate)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188927


  5 / 8968 MEDLINE  
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[PMID]:29277782
[Au] Autor:Radin DP; Purcell R; Lippa AS
[Ad] Endereço:RespireRx Pharmaceuticals, Inc., Glen Rock, NJ, U.S.A. dradin@respirerx.com.
[Ti] Título:Oncolytic Properties of Ampakines .
[So] Source:Anticancer Res;38(1):265-269, 2018 01.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: The 5-year survival rate of glioblastoma (GBM) is ~10%, demonstrating that a new therapeutic modality for this cancer is desperately needed. Complicating the search for such a modality is that most large molecules cannot pass through the blood brain barrier, so molecules demonstrating efficacy in vitro may not be useful in vivo because they never reach the brain. Recently, the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) was identified as an effective agent in targeting GBM in vitro and in vivo by agonizing AMPA-glutamate receptors (AMPARs), eliciting massive calcium influx and mitochondrial calcium overload and apoptosis. MATERIALS AND METHODS: In the current study, we used a colorimetric cell viability assay to determine if we could enhance the oncolytic effect of FLX in vitro by pre-treating cells with an AMPAR-positive allosteric modulator (Ampakine). RESULTS: Our results demonstrated for the first time that concentrations of the Class I ampakine CX614, which increase AMPAR agonist binding affinity, possess oncolytic activity as a sole agent and synergistically reduce GBM viability when paired with FLX. FLX also demonstrates a dose-dependent induction of apoptosis in cancer cells originating outside the CNS that overexpress calcium-permeable AMPARs. Likewise, CX614 inhibits cancer cell viability in a dose-dependent fashion and its combination with FLX synergistically reduces cell viability. These effects of CX614 were not seen with the Class II ampakines, CX717 and CX1739. CONCLUSION: CX614 inhibits the growth of multiple cancers in vitro and bolsters the oncolytic activity of FLX in several cancers.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Fluoxetina/farmacologia
Oxazinas/farmacologia
[Mh] Termos MeSH secundário: Neoplasias Encefálicas/tratamento farmacológico
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Glioblastoma/tratamento farmacológico
Seres Humanos
Receptores de AMPA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Oxazines); 0 (Receptors, AMPA); 01K63SUP8D (Fluoxetine); 87V631480W (2H,3H,6aH-pyrrolidino(2'',1''-3',2')1,3-oxazino(6',5'-5,4)benzo(e)1, 4-dioxan-10-one)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171227
[St] Status:MEDLINE


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[PMID]:29024665
[Au] Autor:Farhy-Tselnicker I; van Casteren ACM; Lee A; Chang VT; Aricescu AR; Allen NJ
[Ad] Endereço:Salk Institute for Biological Studies, Molecular Neurobiology Laboratory, 10010 North Torrey Pines Rd, La Jolla, CA 92037, USA.
[Ti] Título:Astrocyte-Secreted Glypican 4 Regulates Release of Neuronal Pentraxin 1 from Axons to Induce Functional Synapse Formation.
[So] Source:Neuron;96(2):428-445.e13, 2017 Oct 11.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The generation of precise synaptic connections between developing neurons is critical to the formation of functional neural circuits. Astrocyte-secreted glypican 4 induces formation of active excitatory synapses by recruiting AMPA glutamate receptors to the postsynaptic cell surface. We now identify the molecular mechanism of how glypican 4 exerts its effect. Glypican 4 induces release of the AMPA receptor clustering factor neuronal pentraxin 1 from presynaptic terminals by signaling through presynaptic protein tyrosine phosphatase receptor δ. Pentraxin then accumulates AMPA receptors on the postsynaptic terminal forming functional synapses. Our findings reveal a signaling pathway that regulates synaptic activity during central nervous system development and demonstrates a role for astrocytes as organizers of active synaptic connections by coordinating both pre and post synaptic neurons. As mutations in glypicans are associated with neurological disorders, such as autism and schizophrenia, this signaling cascade offers new avenues to modulate synaptic function in disease.
[Mh] Termos MeSH primário: Astrócitos/secreção
Axônios/secreção
Proteína C-Reativa/secreção
Proteoglicanas de Heparan Sulfato/secreção
Proteínas do Tecido Nervoso/secreção
Sinapses/secreção
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Astrócitos/metabolismo
Axônios/metabolismo
Proteína C-Reativa/genética
Proteína C-Reativa/metabolismo
Células Cultivadas
Feminino
Células HEK293
Proteoglicanas de Heparan Sulfato/fisiologia
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Ratos
Ratos Sprague-Dawley
Receptores de AMPA/metabolismo
Células Ganglionares da Retina/metabolismo
Células Ganglionares da Retina/secreção
Sinapses/genética
Sinapses/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gpc4 protein, mouse); 0 (Heparan Sulfate Proteoglycans); 0 (Nerve Tissue Proteins); 0 (Receptors, AMPA); 0 (neuronal pentraxin); 9007-41-4 (C-Reactive Protein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE


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[PMID]:29023523
[Au] Autor:Hübel N; Hosseini-Zare MS; Ziburkus J; Ullah G
[Ad] Endereço:Department of Physics, University of South Florida, Tampa, Florida, United States of America.
[Ti] Título:The role of glutamate in neuronal ion homeostasis: A case study of spreading depolarization.
[So] Source:PLoS Comput Biol;13(10):e1005804, 2017 Oct.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Simultaneous changes in ion concentrations, glutamate, and cell volume together with exchange of matter between cell network and vasculature are ubiquitous in numerous brain pathologies. A complete understanding of pathological conditions as well as normal brain function, therefore, hinges on elucidating the molecular and cellular pathways involved in these mostly interdependent variations. In this paper, we develop the first computational framework that combines the Hodgkin-Huxley type spiking dynamics, dynamic ion concentrations and glutamate homeostasis, neuronal and astroglial volume changes, and ion exchange with vasculature into a comprehensive model to elucidate the role of glutamate uptake in the dynamics of spreading depolarization (SD)-the electrophysiological event underlying numerous pathologies including migraine, ischemic stroke, aneurysmal subarachnoid hemorrhage, intracerebral hematoma, and trauma. We are particularly interested in investigating the role of glutamate in the duration and termination of SD caused by K+ perfusion and oxygen-glucose deprivation. Our results demonstrate that glutamate signaling plays a key role in the dynamics of SD, and that impaired glutamate uptake leads to recovery failure of neurons from SD. We confirm predictions from our model experimentally by showing that inhibiting astrocytic glutamate uptake using TFB-TBOA nearly quadruples the duration of SD in layers 2-3 of visual cortical slices from juvenile rats. The model equations are either derived purely from first physical principles of electroneutrality, osmosis, and conservation of particles or a combination of these principles and known physiological facts. Accordingly, we claim that our approach can be used as a future guide to investigate the role of glutamate, ion concentrations, and dynamics cell volume in other brain pathologies and normal brain function.
[Mh] Termos MeSH primário: Ácido Glutâmico/metabolismo
Modelos Neurológicos
Neurônios/metabolismo
[Mh] Termos MeSH secundário: Animais
Ácido Aspártico/análogos & derivados
Ácido Aspártico/farmacologia
Astrócitos/efeitos dos fármacos
Astrócitos/metabolismo
Encefalopatias/metabolismo
Encefalopatias/patologia
Tamanho Celular
Biologia Computacional
Fenômenos Eletrofisiológicos
Homeostase
Técnicas In Vitro
Canais Iônicos/metabolismo
Masculino
Potenciais da Membrana
N-Metilaspartato/metabolismo
Neurônios/citologia
Ratos
Ratos Sprague-Dawley
Receptores de AMPA/metabolismo
Córtex Visual/efeitos dos fármacos
Córtex Visual/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((2S,3S)-3-(3-(4-(trifluoromethyl)benzoylamino)benzyloxy)aspartate); 0 (Ion Channels); 0 (Receptors, AMPA); 30KYC7MIAI (Aspartic Acid); 3KX376GY7L (Glutamic Acid); 6384-92-5 (N-Methylaspartate)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005804


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[PMID]:28919175
[Au] Autor:Lu HW; Balmer TS; Romero GE; Trussell LO
[Ad] Endereço:Neuroscience Graduate Program, Oregon Health and Science University, Portland, OR, USA.
[Ti] Título:Slow AMPAR Synaptic Transmission Is Determined by Stargazin and Glutamate Transporters.
[So] Source:Neuron;96(1):73-80.e4, 2017 Sep 27.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AMPARs mediate the briefest synaptic currents in the brain by virtue of their rapid gating kinetics. However, at the mossy fiber-to-unipolar brush cell synapse in the cerebellum, AMPAR-mediated EPSCs last for hundreds of milliseconds, and it has been proposed that this time course reflects slow diffusion from a complex synaptic space. We show that upon release of glutamate, synaptic AMPARs were desensitized by transmitter by >90%. As glutamate levels subsequently fell, recovery of transmission occurred due to the presence of the AMPAR accessory protein stargazin that enhances the AMPAR response to low levels of transmitter. This gradual increase in receptor activity following desensitization accounted for the majority of synaptic transmission at this synapse. Moreover, the amplitude, duration, and shape of the synaptic response was tightly controlled by plasma membrane glutamate transporters, indicating that clearance of synaptic glutamate during the slow EPSC is dictated by an uptake process.
[Mh] Termos MeSH primário: Sistema X-AG de Transporte de Aminoácidos/fisiologia
Canais de Cálcio/fisiologia
Ácido Glutâmico/fisiologia
Receptores de AMPA/fisiologia
Transmissão Sináptica/fisiologia
[Mh] Termos MeSH secundário: Animais
Canais de Cálcio/genética
Cerebelo/fisiologia
Potenciais Pós-Sinápticos Excitadores/fisiologia
Camundongos
Camundongos Transgênicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System X-AG); 0 (Cacng2 protein, mouse); 0 (Calcium Channels); 0 (Receptors, AMPA); 3KX376GY7L (Glutamic Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171011
[Lr] Data última revisão:
171011
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE


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[PMID]:28904093
[Au] Autor:Miyazaki K; Ross WN
[Ad] Endereço:Department of Physiology, New York Medical College, Valhalla, New York 10595, and.
[Ti] Título:Sodium Dynamics in Pyramidal Neuron Dendritic Spines: Synaptically Evoked Entry Predominantly through AMPA Receptors and Removal by Diffusion.
[So] Source:J Neurosci;37(41):9964-9976, 2017 Oct 11.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dendritic spines are key elements underlying synaptic integration and cellular plasticity, but many features of these important structures are not known or are controversial. We examined these properties using newly developed simultaneous sodium and calcium imaging with single-spine resolution in pyramidal neurons in rat hippocampal slices from either sex. Indicators for both ions were loaded through the somatic patch pipette, which also recorded electrical responses. Fluorescence changes were detected with a high-speed, low-noise CCD camera. Following subthreshold electrical stimulation, postsynaptic sodium entry is almost entirely through AMPA receptors with little contribution from entry through NMDA receptors or voltage-gated sodium channels. Sodium removal from the spine head is through rapid diffusion out to the dendrite through the spine neck with a half-removal time of ∼16 ms, which suggests the neck has low resistance. Peak [Na ] changes during single EPSPs are ∼5 mm Stronger electrical stimulation evoked small plateau potentials that had significant longer-lasting localized [Na ] increases mediated through NMDA receptors. Dendritic spines, small structures that are difficult to investigate, are important elements in the fundamental processes of synaptic integration and plasticity. The main tool for examining these structures has been calcium imaging. However, the kinds of information that calcium imaging reveals is limited. We used newly developed, high-speed, simultaneous sodium and calcium imaging to examine ion dynamics in spines in hippocampal pyramidal neurons. We found that following single subthreshold synaptic activation most sodium entry was through AMPA receptors and not through NMDA receptors or through voltage-gated sodium channels and that the spine neck is not a significant resistance barrier. Most spine mechanisms are linear. However, regenerative NMDA conductances can be activated with stronger stimulation.
[Mh] Termos MeSH primário: Espinhas Dendríticas/metabolismo
Células Piramidais/metabolismo
Receptores de AMPA/fisiologia
Sódio/metabolismo
Sinapses/fisiologia
[Mh] Termos MeSH secundário: Animais
Cálcio/metabolismo
Difusão
Estimulação Elétrica
Potenciais Pós-Sinápticos Excitadores/fisiologia
Feminino
Técnicas In Vitro
Masculino
Ratos
Ratos Sprague-Dawley
Receptores de N-Metil-D-Aspartato/metabolismo
Canais de Sódio Disparados por Voltagem/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, AMPA); 0 (Receptors, N-Methyl-D-Aspartate); 0 (Voltage-Gated Sodium Channels); 9NEZ333N27 (Sodium); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1758-17.2017


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[PMID]:28904092
[Au] Autor:Palenzuela R; Gutiérrez Y; Draffin JE; Lario A; Benoist M; Esteban JA
[Ad] Endereço:Department of Neurobiology, Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Madrid 28049, Spain, and.
[Ti] Título:MAP1B Light Chain Modulates Synaptic Transmission via AMPA Receptor Intracellular Trapping.
[So] Source:J Neurosci;37(41):9945-9963, 2017 Oct 11.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The regulated transport of AMPA-type glutamate receptors (AMPARs) to the synaptic membrane is a key mechanism to determine the strength of excitatory synaptic transmission in the brain. In this work, we uncovered a new role for the microtubule-associated protein MAP1B in modulating access of AMPARs to the postsynaptic membrane. Using mice and rats of either sex, we show that MAP1B light chain (LC) accumulates in the somatodendritic compartment of hippocampal neurons, where it forms immobile complexes on microtubules that limit vesicular transport. These complexes restrict AMPAR dendritic mobility, leading to the intracellular trapping of receptors and impairing their access to the dendritic surface and spines. Accordingly, increasing MAP1B-LC expression depresses AMPAR-mediated synaptic transmission. This effect is specific for the GluA2 subunit of the AMPAR and requires glutamate receptor interacting protein 1 (GRIP1) interaction with MAP1B-LC. Therefore, MAP1B-LC represents an alternative link between GRIP1-AMPARs and microtubules that does not result in productive transport, but rather limits AMPAR availability for synaptic insertion, with a direct impact on synaptic transmission. The ability of neurons to modify their synaptic connections, known as synaptic plasticity, is accepted as the cellular basis for learning and memory. One mechanism for synaptic plasticity is the regulated addition and removal of AMPA-type glutamate receptors (AMPARs) at excitatory synapses. In this study, we found that a microtubule-associated protein, MAP1B light chain (MAP1B-LC), participates in this process. MAP1B-LC forms immobile complexes along dendrites. These complexes limit intracellular vesicular trafficking and trap AMPARs inside the dendritic shaft. In this manner, MAP1B restricts the access of AMPARs to dendritic spines and the postsynaptic membrane, contributing to downregulating synaptic transmission.
[Mh] Termos MeSH primário: Proteínas Associadas aos Microtúbulos/fisiologia
Receptores de AMPA/fisiologia
Sinapses/fisiologia
Transmissão Sináptica/genética
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Animais
Dendritos/efeitos dos fármacos
Espinhas Dendríticas/fisiologia
Feminino
Hipocampo/citologia
Hipocampo/metabolismo
Masculino
Camundongos
Proteínas Associadas aos Microtúbulos/biossíntese
Proteínas Associadas aos Microtúbulos/genética
Proteínas do Tecido Nervoso/metabolismo
Neurônios/metabolismo
Ratos
Ratos Wistar
Receptores de AMPA/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Grip1 protein, mouse); 0 (Microtubule-Associated Proteins); 0 (Nerve Tissue Proteins); 0 (Receptors, AMPA); 0 (glutamate receptor ionotropic, AMPA 1); 0 (glutamate receptor ionotropic, AMPA 2); 0 (microtubule-associated protein 1B)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0505-17.2017



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