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Quantal currents at single-site central synapses

JOURnAL OF PHYSIOLOGY-LOndOn 2000年第1期526卷 3-11页

作者： Auger, C Marty, A UCL Dept Physiol London WC1 E6BT England Max Planck Inst Biophys Chem Arbeitsgrp Zellulare Neurobiol D-37077 Gottingen Germany

The mode of operation of synaptic transmission has been primarily worked out at the vertebrate neuromuscular junction, thus providing a framework for the interpretation of studies at central synapses. However, differences have been found between the two systems, and a coherent model is still lacking for central synapses. Research in this area revolves around several questions. (1) Is the variability of quantal amplitudes determined pre- or postsynaptically? (2) What is the occupancy of postsynaptic receptors following the release of a synaptic vesicle? And (3) does multivesicular release occur at single release sites following one presynaptic action potential? To answer these questions, it is essential to investigate synaptic processes at the level of single release sites. This is technically difficult because of the complex morphology and small dimensions of central synapses. nevertheless significant advances have been made in the past few years.

关键词：动作电位/药物作用苯二氮|艹卓|类/药理学结合竞争性/药物作用细胞培养的中枢神经系统/细胞学中枢神经系统/药物作用中枢神经系统/代谢诱发电位/药物作用兴奋性突触后电位/药物作用谷氨酸/代谢海马/细胞学海马/药物作用海马/代谢神经元/细胞学神经元/药物作用神经元/代谢膜片钳术受体 AMPA/代谢受体 n-甲基-d-天冬氨酸/代谢受体神经递质/拮抗剂和抑制剂受体神经递质/代谢蜘蛛毒液类/药理学突触/药物作用突触/代谢脊椎动物动物

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dynamin-dependent endocytosis of ionotropic glutamate receptors

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PROCEEdInGS OF THE nATIOnAL ACAdEMY OF SCIEnCES OF THE UnITEd STATES OF AMERICA 1999年第24期96卷 14112-14117页

作者： Carroll, RC Beattie, EC Xia, HH Lüscher, C Altschuler, Y nicoli, RA Malenka, RC von Zastrow, M Univ Calif San Francisco Dept Psychiat San Francisco CA 94143 USA Univ Calif San Francisco Dept Mol & Cellular Pharmacol San Francisco CA 94143 USA Univ Calif San Francisco Dept Anat San Francisco CA 94143 USA Univ Calif San Francisco Dept Physiol San Francisco CA 94143 USA

Little is known about the mechanisms that regulate the number of ionotropic glutamate receptors present at excitatory synapses. Herein, we show that GluR1-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) are removed from the postsynaptic plasma membrane of cultured hippocampal neurons by rapid, ligand-induced endocytosis. Although endocytosis of AMPARs can he induced by high concentrations of AMPA without concomitant activation of n-methyl-d-aspartate (nMdA) receptors (nMdARs), nMdAR activation is required for detectable endocytosis induced by synaptically released glutamate, Activated AMPARs colocalize with AP2. a marker of endocytic coated pits, and endocytosis of AMPARs is blocked by biochemical inhibition of clathrin-coated pit function or overexpression of a dominant-negative mutant form of dynamin. These results establish that ionotropic receptors are regulated by dynamin-dependent endocytosis and suggest an important role of endocytic membrane trafficking in the postsynaptic modulation of neurotransmission.

关键词：衔接蛋白复合物2 衔接蛋白复合物α亚单位衔接蛋白质类膜泡运输细胞培养的动力蛋白质类胞吞作用/生理学 GTP磷酸水解酶类/遗传学 GTP磷酸水解酶类/代谢海马/细胞学配体膜蛋白质类/代谢神经元/细胞学神经元/代谢受体 AMPA/代谢受体 n-甲基-d-天冬氨酸/代谢 α-氨基-3-羟基-5-甲基-4-异唑丙酸/代谢动物大鼠

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Laminar and temporal heterogeneity of nMdA/metabotropic glutamate receptor binding in posterior cingulate cortex

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JOURnAL OF nEUROPHYSIOLOGY 2000年第4期84卷 1881-1887页

作者： Hedberg, TG Sperber, EF Velísková, J Moshé, SL Albert Einstein Coll Med Dept Neurol Bronx NY 10461 USA Albert Einstein Coll Med Dept Neurosci Bronx NY 10461 USA Albert Einstein Coll Med Dept Pediat Bronx NY 10461 USA Montefiore Med Ctr Ctr Epilepsy Management Bronx NY 10461 USA Mercy Coll Dobbs Ferry NY 10522 USA Novartis Pharmaceut E Hanover NJ 07936 USA

Both n-methyl-d-aspartate (nMdA) and quisqualate/AMPA-insensitive metabotropic glutamate (mGlu) receptors mediate plasticity induction in neocortex, but their interlaminar distribution in cortical microcircuits is largely unknown. We used (+)H-3-MK801 and H-3-glutamate binding plus saturating concentrations of nMdA, AMPA, and quisqualate to autoradiographically map nMdA and mGlu receptor sites by lamina in posterior cingulate cortex in adult male rats. Specific binding at nMdA receptor sites in laminae II/III and VI was significantly reduced in comparison to other laminae. Brains prepared from rats killed during dark phase of a 12h/12h light/dark cycle showed a mean 129% increase in overall (+)H-3-MK801 binding versus light phase brains but retained reduced binding densities in laminae II/III and VI. In contrast to nMdA findings, specific binding at mGlu sites was consistently elevated during light phase in both laminae II/III and VI. Specific H-3-glutamate binding in dark-phase brains showed an overall 147% increase versus light phase binding but did not retain significant interlaminar heterogeneity. Interpreted in accordance with our physiologically derived models of hippocampo-cortical microcircuitry, these results suggest that spatial and temporal variations in glutamate receptor distribution may play an important role in intracingulate neural processing of afferent input from hippocampus.

关键词：黑暗扣带回/代谢光光照期大鼠 Sprague-dawley 受体亲代谢性谷氨酸盐/代谢受体 n-甲基-d-天冬氨酸/代谢时间因素组织分布动物男(雄)性大鼠

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Preservation of n-methyl-d-aspartate receptor binding sites with age in rat neocortex

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JOURnALS OF GEROnTOLOGY SERIES A-BIOLOGICAL SCIEnCES And MEdICAL SCIEnCES 2000年第11期55卷 B530-B532页

作者： Palmer, AM Univ Pittsburgh Sch Med Dept Psychiat Pittsburgh PA USA Univ Pittsburgh Sch Med Dept Pharmacol Pittsburgh PA USA

This study used [H-3]dizocilpine ([H-3]MK-801) binding to examine glycine, polyamine, and zinc subsites of the n-methyl-d-aspartate (nMdA) receptor in well-washed membranes derived from the neocortex of Fischer 344/norwegian brown rats aged 3, 12, 24 and 37 months. [H-3]dizocilpine binding in the presence of 100 muM glutamate was enhanced by the addition of 30 muM glycine. Binding in the presence of both glutamate and glutamate plus glycine were unaffected by age. The competitive polyamine site antagonist arcaine inhibited [H-3]dizocilpine binding in a dose-dependent fashion and 50 muM spermidine caused a rightward shift in this dose response curve. IC50 values derived from these plots were not significantly affected by age. Similarly, zinc inhibited binding in a dose-dependent fashion and was also unaffected by age. These data indicate that the nMdA receptor is spared in aging.

关键词：衰老/代谢结合部位地卓西平马来酸盐/代谢剂量效应关系药物新皮质/代谢大鼠近交Bn 大鼠近交F344 大鼠 Sprague-dawley 受体 n-甲基-d-天冬氨酸/代谢锌/药理学动物大鼠

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Alzheimer's Congress - drug shows promise for advanced disease

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SCIEnCE 2000年第5478期289卷 375-+页

作者： Marx, J

Although the b-amyloid vaccine now being explored as a potential Alzheimer"s therapy attracted the bulk of the attention at the World Alzheimer Congress 2000 (see previous story), another, more conventional, drug is showing promise in clinical trials. A neuropsychiatrist reported at the "hot topics" session of the congress that the drug memantine, which has been used in Germany for 10 years to treat dementias, significantly slowed the progression of Alzheimer"s symptoms in patients with moderately severe disease.

关键词：阿尔茨海默病/药物疗法疾病恶化兴奋性氨基酸拮抗剂/治疗应用美金刚/治疗应用受体 n-甲基-d-天冬氨酸/拮抗剂和抑制剂受体 n-甲基-d-天冬氨酸/代谢美国人类

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Serotonergic inhibition of action potential evoked calcium transients in nOS-containing mesopontine cholinergic neurons

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JOURnAL OF nEUROPHYSIOLOGY 2000年第3期84卷 1558-1572页

作者： Leonard, CS Rao, SR Inoue, T New York Med Coll Dept Physiol Valhalla NY 10595 USA

nitric oxide synthase (nOS)-containing mesopontine cholinergic (MPCh) neurons of the laterodorsal tegmental nucleus (LdT) are hypothesized to drive the behavioral states of waking and REM sleep through a tonic increase in firing rate which begins before and is maintained throughout these states. In principle, increased firing could elevate intracellular calcium levels and regulate numerous cellular processes including excitability, gene expression, and the activity of neuronal nOS in a state-dependent manner. We investigated whether repetitive firing, evoked by current injection and n-methyl-d-aspartate (nMdA) receptor activation, produces somatic and proximal dendritic [Ca2+](i) transients and whether these transients are modulated by serotonin, a transmitter thought to play a critical role in regulating the state-dependent firing of MPCh neurons. [Ca2+](i) was monitored optically from neurons filled with Ca2+ indicators in guinea pig brain slices while measuring membrane potential with sharp microelectrodes or patch pipettes. neither hyperpolarizing current steps nor subthreshold depolarizing steps altered [Ca2+](i). In contrast, suprathreshold currents caused large and rapid increases in [Ca2+](i) that were related to firing rate. TTX (1 mu M) strongly attenuated this relation. Addition of tetraethylammonium (TEA, 20 mM), which resulted in Ca2+ spiking on depolarization, restored the change in [Ca2+](i) to pre-TTX levels. Suprathreshold doses of nMdA also produced increases in [Ca2+](i) that were reduced by up to 60% by TTX. Application of 5-HT, which hyperpolarized LdT neurons without detectable changes in [Ca2+](i), suppressed both current- and nMdA-evoked increases in [Ca2+](i) by reducing the number of evoked spikes and by inhibiting spike-evoked Ca2+ transients by similar to 40% in the soma and proximal dendrites. This inhibition was accompanied by a subtle increase in the spike repolarization rate and a decrease in spike width, as expected for inhibition of

关键词：动作电位/药物作用动作电位/生理学钙/代谢胆碱能纤维/代谢树突/代谢剂量效应关系药物电刺激兴奋性氨基酸激动剂/药理学 n-甲基天冬氨酸/拮抗剂和抑制剂 n-甲基天冬氨酸/代谢 n-甲基天冬氨酸/药理学神经抑制/药物作用神经抑制/生理学神经元/细胞学神经元/代谢一氧化氮/代谢膜片钳术脑桥/细胞学脑桥/药物作用脑桥/代谢反应时间/药物作用反应时间/生理学受体 n-甲基-d-天冬氨酸/激动剂受体 n-甲基-d-天冬氨酸/代谢血清素/代谢血清素/药理学河豚毒素/药理学动物女(雌)性豚鼠

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Sensory deprivation without competition yields modest alterations of short-term synaptic dynamics

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PROCEEdInGS OF THE nATIOnAL ACAdEMY OF SCIEnCES OF THE UnITEd STATES OF AMERICA 2000年第23期97卷 12864-12868页

作者： Finnerty, GT Connors, BW Brown Univ Dept Neurosci Div Biol & Med Providence RI 02912 USA

Cortical maps express experience-dependent plasticity. However, the underlying cellular mechanisms remain unclear. We have recently shown that sensory deprivation results in large changes of the short-term dynamics of excitatory synapses at the junction of deprived and spared somatosensory (barrel) cortex, which may contribute to map reorganization. A key issue is whether the alterations in short-term synaptic dynamics are driven by a loss of sensory input or by competition between deprived and spared inputs. Here, we report that short-term dynamics of horizontal pathways in the middle of uniformly deprived cortex change only modestly. Vertical intracortical pathways were unaffected by deprivation. Our results suggest that uniform loss of sensory activity has a limited effect on short-term synaptic dynamics. We concluded that competition between sensory inputs is necessary to produce large-scale changes in synaptic dynamics after sensory deprivation.

关键词：脑/代谢脑/病理学脑图兴奋性突触后电位/生理学受体 GABA/代谢受体 n-甲基-d-天冬氨酸/代谢感觉缺失/生理学躯体感觉皮质/代谢躯体感觉皮质/生理学突触/生理学突触传递/生理学动物大鼠

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EXCITATORY AMInO-ACId RECEPTORS In HUMAn SPInAL-CORd - EVALUATIOn In AMYOTROPHIC-LATERAL-SCLEROSIS PATIEnTS

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AnnALS OF THE nEW YORK ACAdEMY OF SCIEnCES 1992年第1期648卷 260-262页

作者： ALLAOUA, H CHAUdIEU, I BOKSA, P PERRY, TL KRIEGER, C QUIRIOn, R FAC MED VANCOUVER VANCOUVER V6T 1W5BCCANADA MCGILL UNIV DEPT PSYCHIATVERDUN H4H 1R3QUEBECCANADA

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nMdA receptor delayed maturation and schizophrenia

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MEdICAL HYPOTHESES 2000年第5期54卷 693-697页

作者： Ruppin, E Tel Aviv Univ Sch Med Dept Physiol IL-69978 Tel Aviv Israel Tel Aviv Univ Sch Med Dept Comp Sci IL-69978 Tel Aviv Israel Tel Aviv Univ Sch Math IL-69978 Tel Aviv Israel

This paper presents the hypothesis that nMdA receptor delayed maturation (nRdM) may lead to the pathogenesis of schizophrenic psychotic symptoms. This hypothesis is further analyzed in the language of a neural modeling formulation. This formulation points to a possible chain of pathological events, leading from molecular-level nRdM to over-increased synaptic plasticity, and to the formation of pathological attractors, a putative macroscopic-level correlate of schizophrenic positive symptoms. The relations of the nRdM hypothesis to other alterations which are assumed to take place in schizophrenia are discussed, together with possible ways to test this hypothesis. (C) 2000 Harcourt Publishers Ltd.

关键词：神经网蛋白质加工转译后受体 n-甲基-d-天冬氨酸/代谢精神分裂症/代谢人类

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Rapid, synaptically driven increases in the intrinsic excitability of cerebellar deep nuclear neurons

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nATURE nEUROSCIEnCE 2000年第2期3卷 109-111页

作者： Aizenman, Cd Linden, dJ Johns Hopkins Univ Sch Med Dept Neurosci Baltimore MD 21205 USA

The neurons of the cerebellar deep nuclei are implicated in certain forms of motor learning such as associative eyeblink conditioning, partly because increases in their firing rates parallel acquisition of the conditioned response. Here we demonstrate that these neurons can show persistent increases in their intrinsic excitability following a Ca2+ load imposed by synaptic activation of nMdA receptors or direct current injection. This phenomenon, together with use-dependent alterations in synaptic strength, may provide a flexible and informationally rich engram for cerebellar motor learning. [ABSTRACT FROM AUTHOR]

关键词：动作电位/药物作用动作电位/生理学钙/代谢细胞培养的小脑核/细胞学小脑核/生理学电刺激兴奋性突触后电位/药物作用兴奋性突触后电位/生理学 GABA拮抗剂/药理学微电极神经元/细胞学神经元/药物作用神经元/代谢神经元/生理学印防己毒素/药理学喹恶啉类/药理学受体 AMPA/拮抗剂和抑制剂受体 AMPA/代谢受体 n-甲基-d-天冬氨酸/代谢突触/生理学突触传递/药物作用突触传递/生理学动物大鼠

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