Causes and consequences of dysregulated extracellular glutamate signalling after metabolic stress

细胞外谷氨酸稳态的损害或失败是脑缺血病理生理学的中心步骤，因为它导致细胞过度兴奋，从而导致兴奋性毒性。在中风的情况下，据信，例如，谷氨酸的积累和增加的逃逸进入突触外空间及其通过突触外N-甲基-D-天冬氨酸受体的兴奋性毒性作用是细胞损伤和死亡的主要机制。然而，事件的顺序和具体机制，导致扰动谷氨酸信号，急性代谢应激的持续时间和严重程度之间的关系，激活机制和功能变化的细胞外谷氨酸动力学仍然是完全揭示。在第一个资助期的过去两年中，我们发现急性代谢应激根据其严重程度有两种不同的结果。而严重的代谢应激导致细胞外谷氨酸的瞬时激增和突触后场反应的持久抑制，中度代谢应激不会，而是触发突触驱动的细胞外谷氨酸瞬变和突触传递的持续增加。我们建议建立基本的机制和功能的影响。将有三个主要主题：1）细胞和亚细胞特异性失调的细胞外谷氨酸信号，2）谷氨酸信号失调的机制，和3）谷氨酸失调和缺血性长时程增强在体外和体内的相互依赖性。通过探索这些主题，我们将揭示在急性代谢应激和缺血期间和之后细胞外谷氨酸信号改变的新原因和后果。

Impairment or failure of extracellular glutamate homeostasis is a central step in the pathophysiology of brain ischemia because it leads to excessive cellular excitation and thereby to excitotoxicity. In the context of stroke, it is believed for instance that the accumulation and increased escape of glutamate into extrasynaptic space and its excitotoxic action through extrasynaptic N-methyl-D-aspartate receptors is a major mechanism underlying cell damage and death. However, the sequence of events and specific mechanisms that lead to perturbed glutamate signalling, the relationship between duration and severity of acute metabolic stress, the activated mechanisms and the functional changes of extracellular glutamate dynamics remain to be fully uncovered. In the past two years of the 1st funding period, we have discovered that acute metabolic stress has two qualitatively distinct outcomes depending on its severity. Whereas severe metabolic stress leads a transient surge of extracellular glutamate and a lasting suppression of postsynaptic field responses, moderate metabolic stress does not and instead triggers a persistent increase of synaptically driven extracellular glutamate transients and of synaptic transmission. We propose to establish the underlying mechanisms and their functional implications. There will be three main themes: 1) cellular and subcellular specificity of dysregulated extracellular glutamate signalling, 2) mechanisms underlying the dysregulation of glutamate signalling, and 3) interdependence of glutamate dysregulation and ischemic long-term potentiation in vitro and in vivo. By exploring these topics, we will reveal new causes and consequences of altered extracellular glutamate signalling during and after acute metabolic stress and in ischemia.