Department of Pharmacology, Jikei University School of Medicine, Tokyo, Japan.
Department of Psychology and Neuroscience Program, Trinity College, Hartford, Connecticut.
J Neurophysiol. 2019 Aug 1;122(2):721-728. doi: 10.1152/jn.00813.2018. Epub 2019 Jun 26.
Adenosine receptors are widely expressed in the brain, and adenosine is a key bioactive substance for neuroprotection. In this article, we clarify systematically the role of adenosine A receptors during a range of timescales and conditions when a significant amount of adenosine is released. Using acute hippocampal slices obtained from mice that were wild type or null mutant for the adenosine A receptor, we quantified and characterized the impact of varying durations of experimental ischemia, hypoxia, and hypoglycemia on synaptic transmission in the CA1 subregion. In normal tissue, these three stressors rapidly and markedly reduced synaptic transmission, and only treatment of sufficient duration led to incomplete recovery. In contrast, inactivation of adenosine A receptors delayed and/or lessened the reduction in synaptic transmission during all three stressors and reduced the magnitude of the recovery significantly. We reproduced the responses to hypoxia and hypoglycemia by applying an adenosine A receptor antagonist, validating the clear effects of genetic receptor inactivation on synaptic transmission. We found activation of adenosine A receptor inhibited hippocampal synaptic transmission during the acute phase of ischemia, hypoxia, or hypoglycemia and caused the recovery from synaptic impairment after these three stressors using genetic mutant. These studies quantify the neuroprotective role of the adenosine A receptor during a variety of metabolic stresses within the same recording system. Deprivation of oxygen and/or glucose causes a rapid adenosine A receptor-mediated decrease in synaptic transmission in mouse hippocampus. We quantified adenosine A receptor-mediated inhibition during and synaptic recovery after ischemia, hypoxia, and hypoglycemia of varying durations using a genetic mutant and confirmed these findings using pharmacology. Overall, using the same recording conditions, we found the acute response and the neuroprotective ability of the adenosine A receptor depended on the type and duration of deprivation event.
腺苷受体广泛表达于脑内，而腺苷是神经保护的关键生物活性物质。在本文中，我们系统地阐明了在大量释放腺苷的各种时间尺度和条件下，腺苷 A 受体的作用。使用从野生型或腺苷 A 受体缺失突变型小鼠获得的急性海马切片，我们量化并表征了不同持续时间的实验性缺血、缺氧和低血糖对 CA1 亚区突触传递的影响。在正常组织中，这三种应激源迅速且明显地降低了突触传递，只有足够持续时间的处理才能导致不完全恢复。相比之下，腺苷 A 受体失活延迟和/或减轻了这三种应激源下的突触传递减少，并显著降低了恢复幅度。我们通过应用腺苷 A 受体拮抗剂复制了对缺氧和低血糖的反应，验证了基因受体失活对突触传递的明显影响。我们发现，在缺血、缺氧或低血糖的急性阶段，激活腺苷 A 受体抑制海马突触传递，并在这三种应激源后通过遗传突变体引起突触损伤的恢复。这些研究在相同的记录系统中定量评估了腺苷 A 受体在多种代谢应激下的神经保护作用。缺氧和/或葡萄糖剥夺导致小鼠海马中的快速的腺苷 A 受体介导的突触传递减少。我们使用基因突变体量化了不同持续时间的缺血、缺氧和低血糖过程中的腺苷 A 受体介导的抑制作用，并使用药理学方法验证了这些发现。总体而言，我们使用相同的记录条件发现，急性反应和腺苷 A 受体的神经保护能力取决于剥夺事件的类型和持续时间。
