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.

摘要 海马长时程增强（LTP）是突触传递的增强， 是长期记忆存储的基础这种形式的突触可塑性已经在 海马CA 3至CA 1突触。赫布在20世纪40年代预测， LTP的理解是众所周知的，LTP必须依赖于“一些生长过程或 代谢变化”发生在一个或两个细胞，使“A的效率作为一个 细胞放电B增加。”在海马高频刺激后，急性和 持续的生长过程确实发生，包括通过NMDA受体调节Ca 2+通量 进入CA 1神经元，并增强AMPA受体插入突触后膜 但需要改变突触传递效率的代谢变化， 和/或维持LTP从未被发现。在这个应用程序中，我们将测试，如果一个长期的变化， 依赖于Bcl-xL的线粒体效率是LTP发生所必需的。我们发现 先前线粒体在Bcl-2表达后表现出改善的代谢效率， 2家族蛋白Bcl-xL。Bcl-xL在抵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，定位这些 细胞器的突触，并增加突触的数量和大小和速度， 自发性神经递质释放事件。最重要的是，我们发现， Bcl-xL通过其降低线粒体ATP生成的能力来增加线粒体的ATP生成。 在ATP合酶c亚基内发现的泄漏通道打开的可能性。在高处 频率突触刺激时，Bcl-xL移动到线粒体，并在线粒体周围形成ATP光环。 线粒体，这种持续增强的线粒体ATP水平似乎依赖于 在Bcl-xL和LTP所需的。在这项拟议的研究中，我们将确定LTP是否需要一个真正的 线粒体功能效率的变化。我们会考虑， 如果我们发现线粒体的耗氧量相对减少或没有变化， 在增强ATP的生产过程中。我们将确认Bcl-xL靶向ATP合酶是否是 这是ATP生产效率变化所必需的。我们将确定， 线粒体Bcl-xL与海马CA 1区神经元LTP的发生有关最后我们 将确定低电导ATP合成酶c亚基是否会逆转遗传Bcl-2的影响， xL消耗，并将允许LTP的发作和/或维持。