Increasing small conductance Ca2+-activated potassium channel activity reverses ischemia-induced impairment of long-term potentiation

Eur J Neurosci. 2014 Oct;40(8):3179-88. doi: 10.1111/ejn.12683. Epub 2014 Jul 31.


Global cerebral ischemia following cardiac arrest and cardiopulmonary resuscitation (CA/CPR) causes injury to hippocampal CA1 pyramidal neurons and impairs cognition. Small conductance Ca(2+)-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 3 h after recovery from CA/CPR and LTP remained impaired for at least 30 days. Treatment with the SK2 channel agonist 1-Ethyl-2-benzimidazolinone (1-EBIO) at 30 min 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 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 30 days after CA/CPR. Similarly, no change in synaptic NMDA receptor protein levels was observed at 7 or 30 days after CA/CPR. Further, patch-clamp experiments demonstrated no change in functional synaptic NMDA receptors at 7 or 30 days after CA/CPR. Electrophysiology recordings showed that synaptic SK channel activity was reduced for the duration of experiments performed (up to 30 days) 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.

Keywords: cardiac arrest; global cerebral ischemia; hippocampus long-term potentiation; mouse; small conductance Ca2+-activated potassium channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / pharmacology
  • Brain Ischemia / physiopathology*
  • Brain Ischemia / prevention & control
  • Calcium Channel Agonists / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / physiopathology*
  • Long-Term Potentiation* / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, AMPA / physiology
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Small-Conductance Calcium-Activated Potassium Channels / physiology*


  • Benzimidazoles
  • Calcium Channel Agonists
  • Kcnn2 protein, mouse
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Small-Conductance Calcium-Activated Potassium Channels
  • 1-ethyl-2-benzimidazolinone