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家族蛋白在程序性细胞死亡的定向阶段起主要作用。 BCL-2家族蛋白质参与细胞死亡的发生或对细胞凋亡的保护作用。 死亡BCL-xL是BCL-2家族中在脑中表达的主要成员，了解其在脑中的表达， 功能是设计神经保护策略的关键。BCL-xL的水平开始上升， 突触正在大脑中形成然而，在成人神经系统中，BCL-xL水平仍然很高。 即使在没有死亡刺激的情况下，BCL-xL系统也能正常工作，这促使我们假设BCL-xL发挥了 在突触传递中的重要生理作用。我们已经证明重组BCLxL 注射到鱿鱼巨神经节的突触前末梢， 突触受到刺激后释放的神经递质。BCL-xL的这一作用被模仿 注射ATP，其阻断了注射BCL-xL的作用，这表明BCL-xL可能 使更多的ATP迅速用于突触传递。此外，当BCL-XL是 在培养的海马神经元中过度表达，它靶向线粒体，定位这些 细胞器到突触，增加突触的数量和大小， 自发性神经递质释放事件。 高频电刺激后神经递质释放的短时程和长时程增强 刺激是在发育期间和在神经可塑性中发生被充分研究的现象。 突触可塑性的一个重要形式是CA 3-CA 1突触的长时程增强（LTP 在哺乳动物的海马体中刺激引起的变化被认为是 记忆形成的过程我们有强有力的初步证据支持 假设BCl·xl是调节长时程增强所必需的， 神经传递我们假设并有强有力的证据表明 BCl·xl的作用机制是增加ATP的形成和释放， 线粒体在本申请中，我们将测试抑制BCl·xl或降低 BCl-xl表达的调节阻止ATP的操作效率的增加 合酶复合体我们假设这些变化是长期需要的。 高频突触刺激后突触强度的变化，因此我们计划测试 抑制BCl·xl是否阻止l TP。