Increasing small conductance Ca2+-activated potassium channel activity reverses ischemia-induced impairment of long-term potentiation.
Increasing small conductance Ca2+-activated potassium channel activity reverses ischemia-induced impairment of long-term potentiation.
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DOI：
10.1111/ejn.12683
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发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
Herson PS
中科院分区：
文献类型：
--
作者：
Orfila JE;Shimizu K;Garske AK;Deng G;Maylie J;Traystman RJ;Quillinan N;Adelman JP;Herson PS
心脏骤停和心肺复苏（CA/CPR）后的全脑缺血导致海马CA 1区锥体神经元损伤，并损害认知功能。在CA 1锥体神经元中表达的SK2通道已被认为是潜在的保护性靶点。在这里，我们表明，在小鼠中，海马长时程增强（LTP）受损早在3小时后恢复CA/CPR和LTP仍然受损至少30天。CA后30分钟用SK2通道激动剂1-EBIO治疗提供了对可塑性缺陷的持续保护，在CA/CPR恢复后30天LTP维持在对照水平。在CA/CPR后的延迟时间观察到谷氨酸释放概率的最小变化，涉及突触后机制。实时荧光定量RT-PCR结果显示，CA/CPR后7天和30天，NMDA受体mRNA的表达均无明显变化。类似地，在CA/CPR后7或30天没有观察到突触NMDA受体蛋白水平的变化。此外，膜片钳实验表明CA/CPR后7或30天的功能性突触NMDA受体没有变化。电生理学记录显示，突触SK通道活性在进行的实验持续时间内（最多30天）降低，并且令人惊讶的是，用1-EBIO处理不能防止CA/CPR诱导的突触SK通道功能丧失。我们得出结论，CA/CPR引起突触后信号传导的改变，这是通过用SK2激动剂1-EBIO治疗来防止的，这表明SK2通道的激活剂可能是有用的治疗剂，以防止缺血性损伤和认知障碍。
Global cerebral ischemia following cardiac arrest and cardiopulmonary resuscitation (CA/CPR) causes injury to hippocampal CA1 pyramidal neurons and impairs cognition. SK2 channels, expressed in CA1 pyramidal neurons, have been implicated as potential protective targets. Here we show that in mice, hippocampal long-term potentiation (LTP) is impaired as early as 3 hrs after recovery from CA/CPR and that LTP remains impaired for at least 30 days. Treatment with the SK2 channel agonist, 1-EBIO 30 minutes after CA provided sustained protection from plasticity deficits, with LTP being maintained at control levels at 30 days after recovery from CA/CPR. Minimal changes in glutamate release probability were observed at delayed times after CA/CPR, implicating post-synaptic mechanisms. Real-time quantitative RT-PCR indicates that CA/CPR does not cause a loss of NMDA receptor mRNA 7 or 30 days after CA/CPR. Similarly, no change in synaptic NMDA receptor protein levels were observed 7 or 30 days after CA/CPR. Further, patch-clamp experiments demonstrate no change in functional synaptic NMDA receptors 7 or 30 days after CA/CPR. Electrophysiology recordings showed that synaptic SK channel activity is reduced for the duration of experiments performed (up to 30 days) and that surprisingly, treatment with 1-EBIO did not prevent CA/CPR-induced loss of synaptic SK channel function. We conclude that CA/CPR causes alterations in post-synaptic signaling that are prevented by treatment with the SK2 agonist 1-EBIO, indicating that activators of SK2 channels may be useful therapeutic agents to prevent ischemic injury and cognitive impairments.
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