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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

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