Role of BCL-xL in synaptic plasticity in the hippocampus

BCL-xL 在海马突触可塑性中的作用

• 批准号: 7781513
• 负责人: Elizabeth Ann Jonas
• 金额: $ 43.42万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781513
• 关键词: Acute; Adult; Affect; Alzheimer' s Disease; Apoptosis; Brain; Cell Death; Cessation of life; Chemosensitization; Complex; Development; Down-Regulation; Event; Family member; Frequencies; Ganglia; Hippocampus (Brain); Injection of therapeutic agent; Ions; Life; Long-Term Potentiation; Membrane; Metabolic; Metabolism; Mitochondria; Molecular; Multienzyme Complexes; Myxoid cyst; Nervous system structure; Neuronal Plasticity; Neurons; Operative Surgical Procedures; Organelles; Parkinson Disease; Phase; Physiological; Play; Presynaptic Terminals; Prevention; Production; Protein Family; Proteins; Recombinants; Role; Site; Slice; Squid; Stimulus; Stroke; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Variant; Vesicle; Whole-Cell Recordings; design; improved; inhibitor/antagonist; knock-down; memory process; neuroprotection; neurotransmission; neurotransmitter release; overexpression; presynaptic; prevent; response; small hairpin RNA; small molecule

BCL-2 family proteins playa major role in the commitment phase of programmed cell death. BCL-2 family proteins contribute either to the onset of cell death or to the protection against cell death. BCL-xL is the major BCL-2 family member expressed in brain, and understanding its function is key to designing strategies for neuroprotectlon. Levels of BCL-xL begin to rise just as synapses are forming in the brain. BCL-xL levels remain high, however, in the adult nervous system even in the absence of a death stimulus, prompting us to hypothesize that BCL-xL plays an important physiological role in synaptic transmission. We have shown that recombinant BCLxL injected into the presynaptic terminal of squid giant ganglion increases the amount of neurotransmitter released upon a stimulus to the synapse. This action of BCL-xL is mimicked by injection of ATP, which occludes the effects of injection of BCL-xL, suggesting that BCL-xL may make more ATP available acutely for synaptic transmission. Furthermore, when BCL-xL is overexpressed in cultured hippocampal neurons, it targets to mitochondria, localizes these organelles to synapses, increases the number and size of synapses and the rate of spontaneous neurotransmitter release events. Short and long term potentiation of neurotransmitter release after high frequency stimulation are well-studied phenomena that occur during development and in neural plasticity. An important form of synaptic plasticity is long term potentiation (L TP) at the CA3-CA 1 synapse in mammalian hippocampus. Changes induced by stimulation at this site are thought to underlie the processes of memory formation. We have strong preliminary evidence to support the hypothesis that BCl·xl is required for the modulation of long term potentiation of neurotransmission at this synapse. We hypothesize and have strong evidence that one mechanism of action of BCl·xl is to increase the formation and release of ATP by mitochondria. In this application, we will test the concept that inhibition of BCl·xl or down regulation of expression of BCl-xl prevents an increase in efficiency of operation of the ATP synthase enzyme complex. We hypothesize that these changes are required for long term changes in synaptic strength after high frequency synaptic stimulation, therefore we plan to test whether inhibition of BCl·xl prevents l TP.

Bcl-2家族蛋白Playa在程序性细胞死亡的承诺阶段的主要作用。 Bcl-2家族蛋白有助于细胞死亡的发作或对细胞的保护 死亡。 Bcl-XL是在大脑中表达的主要BCL-2家族成员，并了解其 功能是设计神经保护作用策略的关键。 BCL-XL的水平开始上升 突触在大脑中形成。但是，在成年人的神经上，BCl-XL水平仍然很高 系统即使没有死亡刺激，也促使我们假设BCL-XL玩耍 突触传播中的重要物理作用。我们已经表明重组BCLXL 注射到鱿鱼巨型神经节的突触前末端增加了 神经递质在刺激上释放到突触。 BCL-XL的这种动作被模仿 注射ATP，这阻塞了注射BCl-XL的影响，表明BCl-XL可能 使更多的ATP急性用于突触传输。此外，当bcl-xl为 在培养的海马神经元中过表达，它靶向线粒体，将其定位 到突触的细胞器，增加突触的数量和大小和速度 赞助神经递质释放事件。 高频后神经递质释放的短期和长期潜力 刺激是在发育和神经可塑性中发生的充分研究现象。 突触可塑性的一种重要形式是在CA3-CA 1突触处的长期增强（L TP） 在哺乳动物海马中。被认为是由该站点刺激引起的变化是基础的 内存形成的过程。我们有大量的初步证据来支持 假设BCl·XL是对长期电势调制所必需的 该突触时的神经传递。我们假设并有强有力的证据表明 BCl·XL的作用机理是增加ATP的形成和释放 线粒体。在此应用中，我们将测试抑制BCl·XL或向下的概念 BCL-XL表达的调节可防止ATP运行效率的提高 合酶复合物。我们假设长期需要这些更改 高频突触刺激后突触强度的变化，因此我们计划测试 BCl·XL的抑制是否阻止L TP。