Allen Nicola J, Rossi David J, Attwell David
Department of Physiology, University College London, London WC1E 6BT, United Kingdom.
J Neurosci. 2004 Apr 14;24(15):3837-49. doi: 10.1523/JNEUROSCI.5539-03.2004.
GABA release during cerebral energy deprivation (produced by anoxia or ischemia) has been suggested either to be neuroprotective, because GABA will hyperpolarize neurons and reduce release of excitotoxic glutamate, or to be neurotoxic, because activation of GABA(A) receptors facilitates Cl- entry into neurons and consequent cell swelling. We have used the GABA(A) receptors of hippocampal area CA1 pyramidal cells to sense the rise of GABA occurring in simulated ischemia. Ischemia evoked, after several minutes, a large depolarization to approximately -20 mV. Before this "anoxic depolarization," there was an increase in GABA release by exocytosis (spontaneous IPSCs). After the anoxic depolarization, there was a much larger, sustained release of GABA that was not affected by blocking action potentials, vesicular release, or the glial GABA transporter GAT-3 but was inhibited by blocking the neuronal GABA transporter GAT-1. Blocking GABA(A) receptors resulted in a more positive anoxic depolarization but decreased cell swelling at the time of the anoxic depolarization. The influence of GABA(A) receptors diminished in prolonged ischemia because glutamate release evoked by the anoxic depolarization inhibited GABA(A) receptor function by causing calcium entry through NMDA receptors. These data show that ischemia releases GABA initially by exocytosis and then by reversal of GAT-1 transporters and that the resulting Cl- influx through GABA(A) receptor channels causes potentially neurotoxic cell swelling.
在大脑能量剥夺（由缺氧或缺血引起）期间，γ-氨基丁酸（GABA）的释放被认为要么具有神经保护作用，因为GABA会使神经元超极化并减少兴奋性毒性谷氨酸的释放；要么具有神经毒性，因为GABA（A）受体的激活促进氯离子进入神经元并导致细胞肿胀。我们利用海马体CA1区锥体细胞的GABA（A）受体来检测模拟缺血过程中细胞外GABA（[GABA]o）的升高。缺血几分钟后，引发了一个大幅去极化至约 -20 mV。在这种“缺氧去极化”之前，通过胞吐作用（自发性抑制性突触后电流，sIPSCs）GABA释放增加。缺氧去极化后，GABA有一个大得多的持续性释放，它不受阻断动作电位、囊泡释放或胶质细胞GABA转运体GAT - 3的影响，但被阻断神经元GABA转运体GAT - 1所抑制。阻断GABA（A）受体会导致缺氧去极化更正，但在缺氧去极化时细胞肿胀减少。在长时间缺血时，GABA（A）受体的影响减弱，因为缺氧去极化引发的谷氨酸释放通过NMDA受体导致钙离子内流，从而抑制GABA（A）受体功能。这些数据表明，缺血最初通过胞吐作用释放GABA，然后通过GAT - 1转运体逆转来释放，并且由此产生的通过GABA（A）受体通道的氯离子内流会导致潜在的神经毒性细胞肿胀。
