Requirement for enhanced metabolic efficiency in hippocampal LTP

海马 LTP 代谢效率提高的要求

• 批准号: 9429217
• 负责人: Elizabeth Ann Jonas
• 金额: $ 22.99万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9429217
• 关键词: AMPA Receptors; Acute; BCL2 gene; Binding; CRISPR/Cas technology; Cell Death; Cells; Coupling; Defect; Electrodes; Energy Metabolism; Event; Eye; Frequencies; Genetic; Goals; Growth; Hippocampus (Brain); Individual; Inner mitochondrial membrane; Knockout Mice; Learning; Link; Long-Term Potentiation; Maintenance; Measures; Membrane; Memory; Metabolic; Mitochondria; Molecular; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Neurodegenerative Disorders; Neurons; Organelles; Oxygen; Oxygen Consumption; Phosphorylation; Positioning Attribute; Postsynaptic Membrane; Probability; Process; Production; Protein Family; Regulation; Resistance; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Technology; Testing; base; bcl-xlong protein; cancer cell; design; improved; inhibitor/antagonist; long term memory; memory consolidation; mutant; neurotransmitter release; overexpression; oxidation; postsynaptic; prevent; therapy development

Abstract Hippocampal long term potentiation (LTP) is the enhancement of synaptic transmission that may underlie long term memory storage. This form of synaptic plasticity has been highly studied in the hippocampal CA3 to CA1 synapse. Hebb predicted in the 1940s before any molecular understanding of LTP was known, that LTP must be dependent upon “some growth process or METABOLIC change” taking place in one or both cells so that “A's EFFICIENCY as one of the cells firing B is increased.” After high frequency stimulation in the hippocampus, acute and persisting growth processes do occur including regulation of Ca2+ flux through NMDA receptors into the CA1 neuron, and enhanced insertion of AMPA receptors into the postsynaptic membrane but a METABOLIC change required to alter the EFFICIENCY of synaptic transmission to induce and/or sustain LTP has never been found. In this application we will test if a long term change in mitochondrial efficiency dependent upon Bcl-xL is required for the onset of LTP. We have found previously that mitochondria manifest improved metabolic efficiency upon expression of the Bcl- 2 family protein Bcl-xL. Bcl-xL is highly expressed in cancer cells resistant to cell death, but also contributes to changes in synaptic strength. Bcl-xL targets to mitochondria, localizes these organelles to synapses and increases the number and size of synapses and the rate of spontaneous neurotransmitter release events. Most importantly for this study, we have found that Bcl-xL increases the production of ATP by mitochondria through its ability to decrease the probability of opening of a leak channel found within the ATP synthase c-subunit. Upon high frequency synaptic stimulation, Bcl-xL moves to mitochondria and a halo of ATP forms around the mitochondria, and this persistently enhanced mitochondrial ATP level appears to be dependent on Bcl-xL and required for LTP. In this proposed study, we will determine if LTP requires a true change in efficiency of mitochondrial function. We will consider that there is an increase in efficiency if we find a relative decrease or no change in oxygen consumption by mitochondria during enhanced ATP production. We will confirm if targeting of Bcl-xL to the ATP synthase is required for the change in efficiency of ATP production. We will determine if the association of Bcl-xL with mitochondria is linked to the onset of LTP in hippocampal CA1 neurons. Finally, we will determine if a low conductance ATP synthase c-subunit will reverse the effects of genetic Bcl- xL depletion, and will allow for the onset and/or maintenance of LTP.

抽象的 海马长期增强（LTP）是突触传播的增强 长期内存存储的基础。这种突触可塑性在 海马CA3至CA1突触。 HEBB在1940年代预测任何分子之前 了解LTP的了解，LTP必须取决于“某些增长过程或 代谢变化在一个或两个细胞中进行，因此“ A的效率是其中之一 在海马，急性和 确实发生了持续的生长过程，包括通过NMDA受体调节Ca2+通量 进入CA1神经元，并增强AMPA受体插入突触后膜 但是，需要改变突触传播效率以诱导的代谢变化 和/或Sustain LTP从未找到。在此应用程序中，我们将测试长期更改 LTP发作需要取决于BCl-XL的线粒体效率。我们找到了 以前，线粒体在表达BCl-表达时表现出提高的代谢效率 2家族蛋白BCL-XL。 Bcl-XL在抗细胞死亡的癌细胞中高度表达，但也 有助于突触强度的变化。 BCL-XL靶向线粒体，将其定位 细胞器以突触并增加突触的数量和大小和速度 赞助神经递质释放事件。对于这项研究，最重要的是，我们发现 BCL-XL通过降低线粒体的能力来增加线粒体的ATP产生 在ATP合酶C-Subunit中发现泄漏通道的概率。高 频率突触刺激，BCL-XL移至线粒体，并在周围的ATP晕。 线粒体，这种持续增强的线粒体ATP水平似乎是依赖性的 在BCL-XL上，需要LTP。在这项拟议的研究中，我们将确定LTP是否需要真实 线粒体功能效率的变化。我们将考虑有所增加 效率如果我们发现线粒体的氧气消耗相对下降或没有变化 在增强的ATP生产过程中。我们将确认将BCl-XL靶向ATP合酶是否为 ATP生产效率的变化所需。我们将确定是否关联 带有线粒体的BCl-XL与海马CA1神经元中LTP的发作有关。最后，我们 将确定低电导ATP合酶C-亚基是否会逆转遗传BCL-的影响 XL耗竭，并允许LTP的发作和/或维护。