期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 40, 期 8, 页码 3179-3188出版社
WILEY-BLACKWELL
DOI: 10.1111/ejn.12683
关键词
cardiac arrest; global cerebral ischemia; hippocampus long-term potentiation; mouse; small conductance Ca2+-activated potassium channels
资金
- NIH [NS065855, NS080851]
- Walter S. and Lucienne Driskill Foundation
- AHA-Philips Resuscitation Fellowship [12POST11930031]
Global cerebral ischemia following cardiac arrest and cardiopulmonary resuscitation (CA/CPR) causes injury to hippocampal CA1 pyramidal neurons and impairs cognition. Small conductance Ca2+-activated potassium channels type 2 (SK2), expressed in CA1 pyramidal neurons, have been implicated as potential protective targets. Here we showed that, in mice, hippocampal long-term potentiation (LTP) was impaired as early as 3h after recovery from CA/CPR and LTP remained impaired for at least 30days. Treatment with the SK2 channel agonist 1-Ethyl-2-benzimidazolinone (1-EBIO) at 30min after CA provided sustained protection from plasticity deficits, with LTP being maintained at control levels at 30days 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 reverse transcriptase-polymerase chain reaction indicated that CA/CPR did not cause a loss of N-methyl-D-aspartate (NMDA) receptor mRNA at 7 or 30days after CA/CPR. Similarly, no change in synaptic NMDA receptor protein levels was observed at 7 or 30days after CA/CPR. Further, patch-clamp experiments demonstrated no change in functional synaptic NMDA receptors at 7 or 30days after CA/CPR. Electrophysiology recordings showed that synaptic SK channel activity was reduced for the duration of experiments performed (up to 30days) and that, surprisingly, treatment with 1-EBIO did not prevent the CA/CPR-induced loss of synaptic SK channel function. We concluded that CA/CPR caused alterations in post-synaptic signaling that were 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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