Astroglial Glutamate Transporters, Calcium, and Mitochondria

星形胶质细胞谷氨酸转运蛋白、钙和线粒体

• 批准号: 9518087
• 负责人: Michael Byrne Robinson
• 金额: $ 54.61万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2018-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9518087
• 关键词: Acute; Adaptor Signaling Protein; Affect; Anatomy; Astrocytes; Attenuated; Back; Biology; Blood Vessels; Blood flow; Calcium; Calcium Signaling; Caliber; Cells; Confocal Microscopy; Coupling; Data; Dendritic Spines; Excitatory Synapse; Functional disorder; Funding; GLAST Protein; Glial Fibrillary Acidic Protein; Glucose; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Hippocampus (Brain); Image; Label; Learning; Length; Lesion; Location; Mediating; Metabolic; Microscopy; Mitochondria; Monitor; Nerve; Nervous system structure; Neuraxis; Neurons; Neurotransmitters; Nitric Oxide Synthase; Oxygen; PINK1 gene; Pathologic; Pathology; Pathway interactions; Positioning Attribute; Process; Proliferation Marker; Protein-Serine-Threonine Kinases; Proteins; Ranvier' s Nodes; Role; Shapes; Signal Transduction; Site; Slice; Stress; Stroke; Synapses; Synaptic Transmission; System; Testing; Time; Traumatic Brain Injury; arteriole; deprivation; excitotoxicity; extracellular; in vivo; inhibitor/antagonist; multi-photon; neuron loss; neurovascular; neurovascular coupling; operation; parkin gene/protein; presynaptic; prevent; response; ubiquitin ligase; uptake; vector

Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system. Acute insults to the nervous system, such as stroke or traumatic brain injury, cause an increase in extracellular glutamate, excessive activation of glutamate receptors, and neuronal death through a process called excitotoxicity. Excitatory synaptic transmission is also an energy consuming process. In fact, increases in excitatory activity cause an increase in blood flow to meet energetic demands imposed by this excitatory activity. Compared to most other neurotransmitters, glutamate is relatively uniquely cleared into astrocytes rather than being directly recycled back into the nerve terminal. Two Na+-dependent glutamate transporters, GLT-1 and GLAST (also called EAAT2 and EAAT1), are almost exclusively expressed by astrocytes. In astrocytes, expression of GLT-1 and GLAST is enriched on fine processes near synapses. During our first funding cycle, we studied the co-compartmentalization of GLT-1 and GLAST with mitochondria. We demonstrated mitochondria are found throughout these processes, they are mobile, and the percentage of mobile mitochondria is regulated by neuronal activity. Furthermore, we demonstrated that inhibition of glutamate transport or inhibition of reversed operation of the Na+/Ca2+ exchanger increases the percentage of mobile mitochondria; we showed that these effects are accompanied by a decrease in basal Ca2+ in astrocyte processes. We developed several lines of evidence that strongly suggest that mitochondria shape spontaneous Ca2+ spikes (amplitude, duration, and spread) in astrocyte processes. We showed that oxygen glucose deprivation causes a loss of mitochondria from astrocytic processes. We showed that inhibition of glutamate transport or inhibition of the reversed operation of the Na+/Ca2+ exchanger blocks this loss of mitochondria. Our data suggest that the elevations in extracellular glutamate observed with acute insults, such as stroke, cause a loss of astrocytic mitochondria. The mechanism by which glutamate transporters cause this loss of mitochondria has not been defined, and it is not clear if this loss has pathologic consequences. In this renewal, we will define the mechanisms involved in this loss of mitochondria and determine if this loss contributes to the pathologic consequences of stroke. We will also determine if glial glutamate transport, reversed Na+/Ca2+ exchange, and mitochondria control the increase in blood flow observed with excitatory neuronal activity.

谷氨酸是哺乳动物中枢神经系统中主要的兴奋性神经递质。急性 对神经系统的侮辱，如中风或创伤性脑损伤，会导致细胞外细胞外的增加 谷氨酸，谷氨酸受体的过度激活，以及通过一个称为 兴奋性毒性。兴奋性突触传递也是一个耗能的过程。事实上，增加的 兴奋性活动导致血液流量增加，以满足这种兴奋性所施加的能量需求 活动。与大多数其他神经递质相比，谷氨酸相对独特地清除到星形胶质细胞中。 而不是被直接循环回神经末梢。两个钠离子依赖的谷氨酸转运体， GLT-1和GLAST(又称EAAT2和EAAT1)几乎只由星形胶质细胞表达。在……里面 在星形胶质细胞中，GLT-1和GLAST的表达主要集中在突触附近的细小突起。 在我们的第一个资金周期中，我们研究了GLT-1和GLAST与线粒体的共同区划。 我们证明了线粒体在这些过程中被发现，它们是可移动的，并且 移动的线粒体受神经元活动的调节。此外，我们还证明了抑制 谷氨酸转运或抑制Na+/Ca~(2+)交换器的反向操作会增加 移动的线粒体；我们发现这些效应伴随着星形胶质细胞基础钙离子的减少。 流程。我们找到了几条证据，有力地表明线粒体的形状 星形胶质细胞突起中自发的钙尖峰(幅度、持续时间和扩散)。我们证明了氧气 缺糖会导致星形细胞突起的线粒体丢失。我们证明了抑制 谷氨酸转运或抑制Na+/Ca~(2+)交换器的反向操作可阻止这种损失 线粒体。我们的数据表明，在急性损伤下观察到的细胞外谷氨酸的升高，如 中风时，会造成星形细胞线粒体的丢失。谷氨酸转运体导致这种情况的机制 线粒体的丢失还没有定义，也不清楚这种丢失是否有病理后果。在这 更新，我们将定义这种线粒体丢失的机制，并确定这种丢失 导致中风的病理后果。我们还将确定神经胶质谷氨酸运输， 逆转Na+/Ca~(2+)交换，线粒体控制兴奋性血流量增加 神经元活动。