Rapid regulation of tonic GABA currents in cultured rat hippocampal neurons
Rapid regulation of tonic GABA currents in cultured rat hippocampal neurons
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DOI：
10.1152/jn.00460.2012
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发表时间：
2013-02-01
影响因子：
2.5
通讯作者：
Richerson, George B.
中科院分区：
文献类型：
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作者：
Ransom, Christopher B.;Tao, Wucheng;Richerson, George B.
兰瑟姆·CB，陶伟，吴勇，西班牙WJ，里切森GB。培养大鼠海马神经元紧张性GABA电流的快速调节。神经生理学杂志109：803-812,2013。2012年10月31日首次出版；DOI：10.1152/jn.00460.2012。-强直性GABA能抑制的亚急性和慢性变化发生在人类和实验性癫痫中。关于紧张性抑制是如何在较短的时间范围(秒)内被调制的，我们知之甚少。我们测量了培养的大鼠海马神经元的内源性紧张性GABA电流，以评估它们是如何受到1)细胞外GABA浓度([GABA])的短暂增加，2)突触后短暂去极化，以及3)突触前细胞去极化的影响。瞬时增加[GABA](1微米)可减少紧张性电流；这种减少是由GABA引起的GABA电流反转电位(E-GABA)的移动所致。突触后神经元的短暂去极化逆转了外源性GABA和增强的紧张性电流的作用。紧张性GABA电流的电压依赖性增强与E-GABA位移无关，表现为后去极化增强(PDP)，这是GABA(A)受体的固有特性(Ransom CB，Wu Y，Richerson GB)。J Neurosci 30：7672-7684,2010)。刀豆素A(ConA)抑制囊泡GABA释放不影响紧张性电流。在ConA处理的细胞中，短暂地施加12 mM K+去极化突触前神经元和神经胶质细胞，使紧张性电流幅度持续增加。SKF89976a(40mM)可逆地抑制K+引起的张力性电流增加，表明这是由GABA转运体1(GAT1)非囊性释放GABA引起的。GAT1逆转导致的非囊泡性GABA释放也出现在急性海马脑片中。我们的结果表明，GABA引起的细胞内氯离子浓度、突触外GABA(A)受体的PDP和非囊泡性GABA释放的变化可以快速调节紧张性GABA电流。这些机制可能会影响癫痫发作期间的紧张性抑制，此时神经元强烈去极化，细胞外GABA和K+浓度升高。
Ransom CB, Tao W, Wu Y, Spain WJ, Richerson GB. Rapid regulation of tonic GABA currents in cultured rat hippocampal neurons. J Neurophysiol 109: 803-812, 2013. First published October 31, 2012; doi:10.1152/jn.00460.2012.-Subacute and chronic changes in tonic GABAergic inhibition occur in human and experimental epilepsy. Less is known about how tonic inhibition is modulated over shorter time frames (seconds). We measured endogenous tonic GABA currents from cultured rat hippocampal neurons to evaluate how they are affected by 1) transient increases in extracellular GABA concentration ([GABA]), 2) transient postsynaptic depolarization, and 3) depolarization of presynaptic cells. Transient increases in [GABA] (1 mu M) reduced tonic currents; this reduction resulted from GABA-induced shifts in the reversal potential for GABA currents (E-GABA). Transient depolarization of postsynaptic neurons reversed the effects of exogenous GABA and potentiated tonic currents. The voltage-dependent potentiation of tonic GABA currents was independent of E-GABA shifts and represented postdepolarization potentiation (PDP), an intrinsic GABA(A) receptor property (Ransom CB, Wu Y, Richerson GB. J Neurosci 30: 7672-7684, 2010). Inhibition of vesicular GABA release with concanamycin A (ConA) did not affect tonic currents. In ConA-treated cells, transient application of 12 mM K+ to depolarize presynaptic neurons and glia produced a persistent increase in tonic current amplitude. The K+-induced increase in tonic current was reversibly inhibited by SKF89976a (40 mu M), indicating that this was caused by nonvesicular GABA release from GABA transporter type 1 (GAT1). Nonvesicular GABA release due to GAT1 reversal also occurred in acute hippocampal brain slices. Our results indicate that tonic GABA currents are rapidly regulated by GABA-induced changes in intracellular Cl- concentration, PDP of extrasynaptic GABA(A) receptors, and nonvesicular GABA release. These mechanisms may influence tonic inhibition during seizures when neurons are robustly depolarized and extracellular GABA and K+ concentrations are elevated.