Glutamate transporters regulate excitability in local networks in rat neocortex
Glutamate transporters regulate excitability in local networks in rat neocortex
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DOI：
10.1016/j.neuroscience.2004.05.030
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发表时间：
2004-01-01
期刊：
影响因子：
3.3
通讯作者：
Hablitz, JJ
中科院分区：
文献类型：
--
作者：
Campbell, SL;Hablitz, JJ
兴奋性突触后电流（EPSC）在新皮层主要是由谷氨酸受体介导的。兴奋的终止需要谷氨酸在释放后迅速从突触间隙中清除。谷氨酸转运体参与EPSC终止，但摄取抑制对兴奋性神经传递的影响因脑区而异。癫痫样活动主要由局部皮层回路中细胞的同步突触激活介导，推测与谷氨酸的大量释放有关。谷氨酸转运蛋白在调节癫痫样活动中的作用尚未得到解决。在这里，我们研究了谷氨酸转运抑制对大鼠新皮层第II/III层锥体细胞EPSC和癫痫样事件的影响。用DL-苏型-β-苄氧基天冬氨酸（TBOA; 30 μ M）抑制谷氨酸转运蛋白对诱发的、推测为α-氨基-3-羟基-5-甲基-异恶唑丙酸介导的EPSC的振幅或衰减时间没有影响。相反，癫痫样放电的幅度和持续时间明显增强。TBOA还导致诱发癫痫样活动的阈值降低和自发性癫痫样放电发生概率增加。TBOA的作用不被Ⅰ类和Ⅱ类代谢型谷氨酸受体拮抗剂（S）-α-甲基-4-羧基苯甘氨酸或红藻氨酸受体拮抗剂[（3S，4aR，6S，8aR）-6-（（4-羧基苯基）甲基-1，2，3，4，4a，5，6，7，8，8a-十氢异喹啉-3-羧酸]所抑制。D-（-）-2-氨基-5-膦酰基戊酸既能阻止TBOA引起的兴奋性变化，又能阻断已引起的兴奋性变化。二氢红藻氨酸盐（300 μ M）具有与TBOA类似的作用，表明胶质转运蛋白GLT-1的参与。在谷氨酸释放增强的条件下，抑制谷氨酸转运增加了局部网络的兴奋性。我们的研究结果表明，摄取抑制产生细胞外谷氨酸水平的升高和N-甲基-D-天冬氨酸受体的激活。(C)2004年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Excitatory postsynaptic currents (EPSCs) in the neocortex are principally mediated by glutamate receptors. Termination of excitation requires rapid removal of glutamate from the synaptic cleft following release. Glutamate transporters are involved in EPSC termination but the effect of uptake inhibition on excitatory neurotransmission varies by brain region. Epileptiform activity is largely mediated by a synchronous synaptic activation of cells in local cortical circuits, presumably associated with a large release of glutamate. The role of glutamate transporters in regulating epileptiform activity has not been addressed. Here we examine the effect of glutamate transport inhibition on EPSCs and epileptiform events in layer II/III pyramidal cells in rat neocortex. Inhibiting glutamate transporters with DL-threo-beta-benzyloxyaspartic acid (TBOA; 30 muM) had no effect on the amplitude or decay time of evoked, presumably alpha-amino-3-hydroxyl-5-methyl-isoxazolepropionic acid-mediated, EPSCs. In contrast, the amplitude and duration of epileptiform discharges were significantly enhanced. TBOA resulted also in a decreased threshold for evoking epileptiform activity and an increased probability of occurrence of spontaneous epileptiform discharges. TBOA's effects were not inhibited by the group I and 11 metabotropic glutamate receptors antagonist (S)-alpha-methyl-4-carboxyphenylglycine or the kainate receptor antagonist [(3S,4aR, 6S, 8aR)-6-((4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid]. D-(-)-2-amino-5-phosphonovaleric acid could both prevent excitability changes by TBOA and block already induced changes. Dihydrokainate (300 muM) had effects similar to TBOA suggesting involvement of the glial transporter GLT-1. Inhibiting glutamate transport increases local network excitability under conditions where there is an enhanced release of glutamate. Our results indicate that uptake inhibition produces an elevation of extracellular glutamate levels and activation of N-methyl-D-aspartate receptors. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.