Astroglial Glutamate Transporters, Calcium, and Mitochondria

星形胶质细胞谷氨酸转运蛋白、钙和线粒体

基本信息

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
项目类别：
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&apos 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

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&apos 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

展开

项目摘要

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。急性侮辱神经系统，例如中风或脑部损伤，会导致细胞外增加谷氨酸，谷氨酸受体的过度激活和神经元死亡通过称为兴奋性毒性。兴奋性突触传播也是一个能量消耗过程。实际上，增加兴奋活动导致血流增加，以满足这种兴奋性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直接回收回神经终端。两个Na+依赖性谷氨酸转运蛋白， GLT-1和Glast（也称为EAAT2和EAAT1）几乎由星形胶质细胞表达。在星形胶质细胞，GLT-1和GLAST的表达富含在突触附近的细微过程中。在我们的第一个融资周期中，我们研究了GLT-1和Glast与线粒体的共同群体化。我们证明了整个过程中都发现了线粒体，它们是移动的，并且是移动线粒体受神经元活性的调节。此外，我们证明了对 Na+/Ca2+交换器的谷氨酸运输或抑制反转操作增加了百分比移动线粒体；我们表明这些影响伴随着星形胶质细胞中基底Ca2+的降低过程。我们开发了几条证据，强烈暗示线粒体形状星形胶质细胞过程中的自发Ca2+尖峰（幅度，持续时间和扩散）。我们表明氧气葡萄糖剥夺导致星形胶质细胞过程的线粒体丧失。我们表明抑制 Na+/Ca2+交换器的反向操作的谷氨酸转运或抑制这种损失线粒体。我们的数据表明，急性侮辱观察到细胞外谷氨酸的升高，这样作为中风，导致星形细胞线粒体的损失。谷氨酸转运蛋白引起的机制线粒体的损失尚未定义，尚不清楚这种损失是否具有病理后果。在这个续订，我们将定义线粒体损失所涉及的机制，并确定此损失是否有助于中风的病理后果。我们还将确定神经胶质谷氨酸是否转运，反转Na+/Ca2+交换，线粒体控制着兴奋性观察到的血流的增加神经元活性。