Departments of Physiology and.
Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada.
J Neurosci. 2014 Aug 6;34(32):10624-34. doi: 10.1523/JNEUROSCI.0335-14.2014.
Hydrogen peroxide (H2O2), a key reactive oxygen species, is produced at low levels during normal cellular metabolism and at higher concentrations under pathological conditions such as ischemia-reperfusion injury. The mechanisms by which H2O2 contributes to physiological and pathological processes in the brain remain poorly understood. Inhibitory GABA type A (GABAA) receptors critically regulate brain function by generating tonic and synaptic currents; however, it remains unknown whether H2O2 directly modulates GABAA receptor function. Here, we performed patch-clamp recordings, together with pharmacological and genetic approaches, to investigate the effects of H2O2 on GABAA receptor-mediated tonic and synaptic currents recorded in cultured mouse hippocampal neurons and CA1 pyramidal neurons in hippocampal slices. We found that H2O2 caused a dramatic increase in tonic current, whereas synaptic currents were unaffected. This increase in tonic current resulted from an extracellular oxidative reaction, which increased the potency of GABA, but only when GABAA receptors were activated by low concentrations of GABA. Oxygen-glucose deprivation, which produces high endogenous levels of H2O2, similarly increased the tonic current. These results suggest that GABAA receptor-mediated tonic current, which is potentiated by H2O2, might contribute to H2O2-induced brain dysfunction.
过氧化氢（H2O2）是一种关键的活性氧物质，在正常细胞代谢过程中会以低水平产生，在缺血再灌注损伤等病理条件下则会以更高浓度产生。H2O2 如何促进大脑的生理和病理过程，其机制仍不甚清楚。抑制性 GABA 型 A 受体（GABAA 受体）通过产生紧张性和突触电流来严格调节大脑功能；然而，目前尚不清楚 H2O2 是否直接调节 GABAA 受体功能。在这里，我们通过膜片钳记录，以及药理学和遗传学方法，研究了 H2O2 对培养的小鼠海马神经元和海马脑片 CA1 锥体神经元中 GABAA 受体介导的紧张性和突触电流的影响。我们发现 H2O2 导致紧张性电流显著增加，而突触电流不受影响。这种紧张性电流的增加是由于细胞外氧化反应所致，该反应增加了 GABA 的效力，但只有当 GABAA 受体被低浓度的 GABA 激活时才会发生这种情况。氧葡萄糖剥夺会产生高水平的内源性 H2O2，同样会增加紧张性电流。这些结果表明，H2O2 增强的 GABAA 受体介导的紧张性电流可能有助于 H2O2 诱导的脑功能障碍。
