NEUROBIOLOGIC STUDIES OF NEURONS AND GLIA IN CELL CULTURE

细胞培养中神经元和神经胶质细胞的神经生物学研究

基本信息

项目摘要

Summary of work: 1) We have continued our work on the mechanisms underlying Hebbian, activity dependent synapse elimination in an in vitro neuromuscular system. We have shown that this process is dependent on the action of protein kinase C (PKC). We now show that a major target for kinase action during the synapse elimination is the acetyl choline receptor (AChR) on the muscle cell surface at neuromuscular junctional synapses. Treatment of nerve-muscle synapses with TPA, a phorbol ester that activates PKC, produces a decrement in synapse effectiveness and a corresponding increased rate of loss and decrease in the concentration of AChR in the muscle membrane. Prolonged, high doses of TPA produce a down regulation of PKC with a parallel decrease in the effect of the drug on synapse effectiveness and on the levels of AChR at the synapse. There is not a detectable change in the pre- synaptic, neural component of the synaptic apparatus. Biochemical studies of AChR synthesis and degradation indicate that loss of AChR from the muscle is accelerated and the synthesis rate is diminished by TPA treatment and the latter effect may be more pronounced than the former. An activity dependent synapse stabilization or augmentation is a crucial component of any Hebbian model of synaptic plasticity. We find that when synapse loss is induced by TPA this can be blocked (synapses preserved) by low frequency stimulation of the synapses. This preserving effect of activation is blocked by a PKA inhibitor, H-89. This suggests that the positive aspect of the Hebbian model requires the action of PKA. Considerable evidence from the literature indicates that both PKC and PKA phosphorylate the AChR and the differential phosphorylation produced by these two kinases results in different effects on AchR stability. PKC destabilizes while PKA stabilizes the receptor. 2) Theoretical and experimental work on synaptic networks in vitro have shown that one of the key aspects of neuronal physiology determining the properties of networks is the incidence of the neurons within the network that generate spontaneous spiking activity. In the absence of such neurons a network will either exhibit very high rates of firing generated by sustaining excitatory synaptic interactions within the network, or be silent. Most networks in fact show sustained low frequency firing. Some networks show bursty behavior and both theory and experimental analysis indicate that this can be produced by a very low but finite incidence of spontaneously active neurons. 3) Growing axons have been shown to be capable of developing side branches some substantial distance (hundreds of microns) back from the growth cone. This usually happens in response to a stimulus that causes a collapse of the axons growth cone. It can happen to an unstimulated axon that is in contact with a stimulated, collapsing axon. This process may play a role in the efficient ingrowth of axons to their correct central targets. - Synapse elimination, Protein kinase C, Protein kinase A, activity dependent, acetylcholine receptor, neuromuscular junction, in vitro
工作总结:1)在体外神经肌肉系统中,我们继续研究Hebbian,活性依赖的突触消除的机制。我们已经证明,这一过程依赖于蛋白激酶C(PKC)的作用。我们现在发现,在突触消除过程中,激酶作用的一个主要靶点是位于神经肌肉连接突触的肌肉细胞表面的乙酰胆碱受体(AChR)。用能激活PKC的佛波酯TPA处理神经肌肉突触,会导致突触有效性降低,相应地增加AChR的损失率和肌膜上AChR的浓度。长时间、高剂量的TPA会下调PKC,同时该药物对突触有效性和突触上AChR水平的影响也会同时降低。突触装置的突触前神经成分没有可检测到的变化。AChR合成和降解的生化研究表明,TPA处理加速了肌肉中AChR的损失,降低了AChR的合成速度,后者的影响可能比前者更明显。依赖活动的突触稳定或增强是任何突触可塑性的Hebbian模型的关键组成部分。我们发现,当TPA诱导突触丢失时,这可以被突触的低频刺激所阻断(突触被保留)。这种激活的保存作用可被PKA抑制剂H-89阻断。这表明,Hebbian模型的积极方面需要PKA的行动。大量的文献证据表明,PKC和PKA都能使AChR磷酸化,并且这两种酶产生的不同磷酸化对AchR的稳定性有不同的影响。PKC使受体不稳定,而PKA使受体稳定。2)关于体外突触网络的理论和实验工作表明,神经生理学决定网络特性的一个关键方面是网络中产生自发放电活动的神经元的发生率。在没有这种神经元的情况下,一个网络要么表现出通过维持网络内兴奋性突触相互作用而产生的非常高的放电率,要么保持沉默。事实上,大多数电视网都显示出持续的低频率激发。一些网络表现出突发性行为,理论和实验分析都表明,这可能是由非常低但有限的自发活动神经元造成的。3)生长中的轴突已被证明能够在距离生长锥体相当远的地方(数百微米)发育侧枝。这通常发生在对导致轴突生长锥体崩溃的刺激的反应中。它可能发生在未受刺激的轴突与受刺激的、塌陷的轴突接触时。这一过程可能在轴突有效地向其正确的中心靶点生长方面发挥作用。-突触消除,蛋白激酶C,蛋白激酶A,活性依赖,乙酰胆碱受体,神经肌肉接头,体外

项目成果

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PHILLIP G NELSON其他文献

PHILLIP G NELSON的其他文献

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{{ truncateString('PHILLIP G NELSON', 18)}}的其他基金

Neurobiologic Studies Of Neurons & Glia In Cell Culture
神经元的神经生物学研究
  • 批准号:
    6508725
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
NEUROBIOLOGIC STUDIES OF NEURONS AND GLIA IN CELL CULTURE
细胞培养中神经元和神经胶质细胞的神经生物学研究
  • 批准号:
    6432486
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Mechanisms of Neurodevelopment in health and disease
健康和疾病中的神经发育机制
  • 批准号:
    6671763
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Mechanisms of Neurodevelopment in health and disease
健康和疾病中的神经发育机制
  • 批准号:
    6813765
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:

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INFLUENCE OF BIOPERIODICITY ON TUMOR IMMUNOTHERAPY
生物周期性对肿瘤免疫治疗的影响
  • 批准号:
    3195505
  • 财政年份:
    1990
  • 资助金额:
    --
  • 项目类别:
INFLUENCE OF BIOPERIODICITY ON TUMOR IMMUNOTHERAPY
生物周期性对肿瘤免疫治疗的影响
  • 批准号:
    3195504
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    1990
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