Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany.
Department of Physics, University of South Florida, Tampa, United States.
Elife. 2024 Sep 17;13:RP98834. doi: 10.7554/eLife.98834.
Ischemia leads to a severe dysregulation of glutamate homeostasis and excitotoxic cell damage in the brain. Shorter episodes of energy depletion, for instance during peri-infarct depolarizations, can also acutely perturb glutamate signaling. It is less clear if such episodes of metabolic failure also have persistent effects on glutamate signaling and how the relevant mechanisms such as glutamate release and uptake are differentially affected. We modeled acute and transient metabolic failure by using a chemical ischemia protocol and analyzed its effect on glutamatergic synaptic transmission and extracellular glutamate signals by electrophysiology and multiphoton imaging, respectively, in the mouse hippocampus. Our experiments uncover a duration-dependent bidirectional dysregulation of glutamate signaling. Whereas short chemical ischemia induces a lasting potentiation of presynaptic glutamate release and synaptic transmission, longer episodes result in a persistent postsynaptic failure of synaptic transmission. We also observed unexpected differences in the vulnerability of the investigated cellular mechanisms. Axonal action potential firing and glutamate uptake were surprisingly resilient compared to postsynaptic cells, which overall were most vulnerable to acute and transient metabolic stress. We conclude that short perturbations of energy supply lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity well beyond the metabolic incident.
缺血导致大脑中谷氨酸稳态的严重失调和兴奋性细胞损伤。例如，在梗死周围去极化期间发生的能量耗竭的短暂发作也会急性扰乱谷氨酸信号。目前尚不清楚这种代谢失败的发作是否对谷氨酸信号也有持续影响，以及相关机制（如谷氨酸释放和摄取）如何受到不同影响。我们使用化学性缺血方案来模拟急性和短暂的代谢衰竭，并分别通过电生理学和多光子成像来分析其对谷氨酸能突触传递和细胞外谷氨酸信号的影响。我们的实验揭示了谷氨酸信号的一种与持续时间相关的双向失调。虽然短暂的化学性缺血诱导了持续的突触前谷氨酸释放和突触传递的增强，但较长的发作会导致突触传递的持续后突触衰竭。我们还观察到所研究的细胞机制的脆弱性存在意外差异。与后突触细胞相比，轴突动作电位放电和谷氨酸摄取令人惊讶地具有弹性，而后突触细胞总体上对急性和短暂的代谢应激最敏感。我们得出结论，能量供应的短暂干扰会导致突触谷氨酸释放的持续增强，这可能会使谷氨酸兴奋性毒性远远超过代谢事件。
