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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Endogenous GABA_A and GABA_B receptor-mediated electrical suppression is critical to neuronal anoxia tolerance
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Endogenous GABA_A and GABA_B receptor-mediated electrical suppression is critical to neuronal anoxia tolerance

机译：内源性GABA_A和GABA_B受体介导的电抑制对神经元缺氧耐受性至关重要

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Anoxic insults cause hyperexcitability and cell death in mammalian neurons. Conversely, in anoxia-tolerant turtle brain, spontaneous electrical activity is suppressed by anoxia (i.e., spike arrest; SA) and cell death does not occur. The mechanism(s) of SA is unknown but likely involves GABAergic synaptic transmission, because GABA concentration increases dramatically in anoxic turtle brain. We investigated this possibility in turtle cortical neurons exposed to anoxia and/or GABAA/B receptor (GABAR) modulators. Anoxia increased endogenous slow phasic GABAergic activity, and both anoxia and GABA reversibly induced SA by increasing GABA_AR- mediated postsynaptic activity and Cl- conductance, which elimi nated the Cl- driving force by depolarizing membrane potential (~8 mV) to GABA receptor reversal potential (～-81 mV), and dampened excitatory potentials via shunting inhibition. In addi tion, both anoxia and GABA decreased excitatory postsynaptic activity, likely via GABA_BR-mediated inhibition of presynaptic glu tamate release. In combination, these mechanisms increased the stimulation required to elicit an action potential ＞20-fold, and ex citatory activity decreased ＞70% despite membrane potential de polarization. In contrast, anoxic neurons cotreated with GABA_(a+B)R antagonists underwent seizure-like events, deleterious Ca～(2+)influx, and cell death, a phenotype consistent with excitotoxic cell death in anoxic mammalian brain. We conclude that increased endoge nous GABA release during anoxia mediates SA by activating an inhibitory, postsynaptic shunt and inhibiting presynaptic gluta mate release. This represents a natural adaptive mechanism in which to explore strategies to protect mammalian brain from low-oxygen insults.
机译：缺氧损伤导致哺乳动物神经元过度兴奋和细胞死亡。相反，在耐缺氧的turtle脑中，自发的电活动被缺氧抑制（即，穗抑制； SA），并且不会发生细胞死亡。 SA的机制尚不清楚，但可能涉及GABA能突触传递，因为缺氧龟脑中GABA的浓度急剧增加。我们在暴露于缺氧和/或GABAA / B受体（GABAR）调节剂的乌龟皮质神经元中研究了这种可能性。缺氧增加内源性慢相的GABA能活动，缺氧和GABA都通过增加GABA_AR介导的突触后活性和Cl-电导可逆地诱导SA，这通过使膜电位去极化（〜8 mV）消除G-受体逆转电位来消除Cl-驱动力。 （〜-81 mV），并通过分流抑制抑制了兴奋电位。此外，缺氧和GABA均可能通过GABA_BR介导的抑制突触前谷氨酸释放而降低兴奋性突触后活性。综合起来，这些机制增加了引起动作电位＞ 20倍所需的刺激，尽管膜电位发生了极化，但兴奋活性却降低了＞ 70％。相比之下，与GABA_（a + B）R拮抗剂共同作用的缺氧神经元发生了癫痫样事件，有害的Ca〜（2+）大量涌入和细胞死亡，这种表型与缺氧哺乳动物脑中兴奋性毒性细胞死亡一致。我们得出的结论是，缺氧期间内胚层GABA释放的增加通过激活抑制性突触后分流和抑制突触前谷氨酸释放来介导SA。这代表了一种自然的适应机制，在其中探索了保护哺乳动物大脑免受低氧侵害的策略。

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