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: 8476413
• 负责人: Elizabeth Ann Jonas
• 金额: $ 38.53万
• 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: 2009-04-01 至 2013-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8476413
• 关键词: AMPA Receptors; Ablation; Acute; Adult; Affect; Alzheimer' s Disease; BCL1 Oncogene; Behavior; Binding; Cell Death; Cell membrane; Cells; Cessation of life; Chronic; Coupling; Data; Development; DsRed; Dyes; Event; Exposure to; Eye; Fluorescence Resonance Energy Transfer; Frequencies; Functional disorder; Genetic; Goals; Hippocampus (Brain); Image; Kinetics; Learning; Life; Light; Long-Term Potentiation; Measurement; Measures; Membrane; Memory; Mental Depression; Metabolic; Metabolism; Mitochondria; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotransmitters; Oxygen; Parkinson Disease; Phosphorylation; Property; Proteins; Publishing; Rattus; Recombinants; Recovery; Regulation; Role; Slice; Subfamily lentivirinae; Synapses; Synapsins; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Techniques; Vesicle; enzyme pathway; improved; in vivo; inhibitor/antagonist; long term memory; neuronal excitability; overexpression; oxidation; postsynaptic; presynaptic; prevent; research study; response; small hairpin RNA; synaptic depression; therapy development; uptake

DESCRIPTION (provided by applicant): At the hippocampal Schaffer collateral to CA1 synapse long term enhancement of synaptic transmission may underlie memory storage. Synaptic strengthening can become dysfunctional in Alzheimer's disease, Parkinson's Disease and other neurodegenerative disorders as synapses decline or are retracted. One important aspect of synaptic plasticity after frequent activity is the enhanced insertion of AMPA receptors into the postsynaptic plasma membrane. In addition to postsynaptic changes, however, long lasting presynaptic changes occur. During development vesicle pool sizes increase to handle more frequently occurring synaptic events, but the role of long lasting presynaptic plasticity at the adult CA1 synapse after high frequency events has been incompletely studied. One form of presynaptic plasticity is a long lasting change in the rate at which vesicles recover to readily releasable pools. During synaptic activity, a decrease in availability of vesicles for release manifests as synaptic depression; the rate at which vesicle pools recover after synaptic depression affects the response capabilities of the synapse and is therefore amenable to plasticity. We have found previously that the anti-death protein Bcl-xL acts not only to prevent somatic death in neurons, but to prevent synaptic depression acutely and over the long term. In part Bcl-xL functions to enhance the rate of recovery of the readily releasable pool of synaptic vesicles. Our recent preliminary data show that Bcl-xL binds directly to vesicle membranes, enhancing the rate of vesicle re-uptake from the plasma membrane during synaptic activity. In addition to vesicle re-uptake, however, our data also show that Bcl-xL, by its regulation of synaptic metabolism, may affect mobilization of vesicles from the reserve pool. The hypothesis of this application is that Bcl-xL causes long term changes in synaptic strength by enhancing mitochondrial efficiency to increase mobilization of a reserve pool of synaptic vesicles. In this proposal, we will study acute and long term changes in mitochondrial efficiency by measuring ongoing changes in ATP levels and oxygen uptake in living presynaptic boutons undergoing stimulation in hippocampal neurons both in culture and in vivo. Using imaging and recording techniques, we will differentiate the effects of Bcl-xL on vesicle re-uptake at the plasma membrane from those on reserve pool mobilization to determine the effect of mitochondrial efficiency on different vesicle re-accumulation strategies. We will also study the effects of Bcl-x on long term changes in vesicle pool depression brought on by inhibition of neuronal excitability. In contrast to decreased activity, increased synaptic activity may be associated with enhanced ATP availability, directly promoting phosphorylation and activation of downstream targets such as synapsin that rapidly release vesicles from the reserve to the readily releasable pool. Our studies will shed light on basic properties that strengthen the synapse during learning and memory or weaken it during synaptic dysfunction or neurodegeneration.

描述（由申请人提供）：在海马 Schaffer 的 CA1 突触侧支处，突触传递的长期增强可能是记忆存储的基础。在阿尔茨海默病、帕金森病和其他神经退行性疾病中，由于突触衰退或回缩，突触强化可能会出现功能障碍。频繁活动后突触可塑性的一个重要方面是 AMPA 受体插入突触后质膜的增强。然而，除了突触后变化之外，还会发生长期持续的突触前变化。在发育过程中，囊泡池的大小会增加，以处理更频繁发生的突触事件，但高频事件后成体 CA1 突触的持久突触前可塑性的作用尚未完全研究。突触前可塑性的一种形式是囊泡恢复为易于释放池的速率的长期持续变化。在突触活动期间，释放囊泡的可用性减少表现为突触抑制；突触抑制后囊泡池恢复的速度会影响突触的反应能力，因此具有可塑性。我们之前发现，抗死亡蛋白 Bcl-xL 不仅可以防止神经元的体细胞死亡，还可以长期和急性地防止突触抑制。 Bcl-xL 的部分功能是提高易于释放的突触小泡池的恢复速度。我们最近的初步数据表明，Bcl-xL 直接与囊泡膜结合，提高了突触活动期间囊泡从质膜重新摄取的速率。然而，除了囊泡再摄取之外，我们的数据还表明，Bcl-xL 通过调节突触代谢，可能会影响储备池中囊泡的动员。该应用的假设是，Bcl-xL 通过增强线粒体效率来增加突触小泡储备池的动员，从而引起突触强度的长期变化。在本提案中，我们将通过测量在培养物和体内海马神经元中接受刺激的活体突触前布顿中 ATP 水平和摄氧量的持续变化来研究线粒体效率的急性和长期变化。使用成像和记录技术，我们将区分 Bcl-xL 对质膜囊泡再摄取的影响和对储备池动员的影响，以确定线粒体效率对不同囊泡再积累策略的影响。我们还将研究 Bcl-x 对神经元兴奋性抑制引起的囊泡池抑制的长期变化的影响。与活性降低相反，突触活性增加可能与 ATP 可用性增强有关，直接促进下游靶标（例如突触蛋白）的磷酸化和激活，从而将囊泡从储备区快速释放到易于释放的池中。我们的研究将揭示在学习和记忆过程中增强突触或在突触功能障碍或神经退行性变过程中削弱突触的基本特性。