MRS STUDIES OF NEUROTRANSMITTER CYCLING IN HUMAN BRAIN

谷氨酸神经递质的释放依赖于稳定的前体 胞浆谷氨酸浓度。突触引起的谷氨酸丢失 释放会耗尽神经末梢胞浆前体库，除非 由谷氨酸的重新摄取和合成来补偿。胶质细胞摄取 有效地将释放的谷氨酸按顺序从突触裂隙中移除 以维持低ECF浓度的谷氨酸。体内和体外 研究表明，胶质细胞摄取的谷氨酸可以转化为 谷氨酰胺通过谷氨酰胺合成酶。谷氨酰胺从神经胶质细胞中释放出来 到ECF，在那里它被神经元吸收并转化回 通过谷氨酰胺酶的作用产生谷氨酸。尽管扮演着关键的角色 在维持正常大脑功能的谷氨酸/谷氨酰胺循环中，几乎没有 知道这一途径的速率或调节的。最近我们有 在大鼠大脑中开发并测试了一种这种途径的模型 允许从C开始测量谷氨酸/谷氨酰胺循环的速率 谷氨酰胺同位素标记的MRS测量。首要目标是 这笔拨款的目的是确定谷氨酸/谷氨酰胺循环的速率 在正常的人脑皮质中。C-MRS将用于测定谷氨酰胺和 [1-13C]和[2-13C]葡萄糖的谷氨酸同位素标记 拟议的谷氨酸/谷氨酰胺循环模型的关键方面将 通过测定改变血氨的效果来检验 受试者总谷氨酰胺合成和无胸膜谷氨酰胺合成的浓度 伴有轻度肝性脑病。

Glutamate neurotransmitter release depends on a stable precursor cytosolic glutamate concentration. Loss of glutamate by synaptic release will deplete the nerve terminal cytosolic precursor pool unless compensated for by glutamate reuptake and synthesis. Glial uptake efficiently removes released glutamate from the synaptic cleft in order to maintain a low ECF concentration of glutamate. In vivo and in vitro studies indicate that glutamate taken up by glia is converted to glutamine by glutamine synthetase. Glutamine is released from the glia to the ECF where it is taken up by neurons and converted back to glutamate through the action of glutaminase. Despite the critical role of this glutamate/glutamine cycle for normal brain function, little is known about the rate or regulation of this pathway. Recently we have developed and tested in the rat brain a model of this pathway which allows the rate of the glutamate/glutamine cycle to be measured from C MRS measurements of glutamine isotopic labeling. The primary objective of this grant is to determine the rate of the glutamate/glutamine cycle in normal human cortex. C MRS will be used to measured glutamine and glutamate isotopic labeling from infused [1-13C] and [2-13C] glucose. Key aspects of the proposed model of the glutamate/glutamine cycle will be tested through measuring of the effect of altering plasma ammonia concentration on total and anapleurotic glutamine synthesis in subjects with mild hepatic encephalopathy.