title: Increasing small conductance Ca2+-activated potassium channel activity reverses ischemia-induced impairment of long-term potentiation.
abstract: 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.
authors: Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA.
authors: J E
authors: JE
authors: Orfila
authors: K
authors: K
authors: Shimizu
authors: A K
authors: AK
authors: Garske
authors: G
authors: G
authors: Deng
authors: J
authors: J
authors: Maylie
authors: R J
authors: RJ
authors: Traystman
authors: N
authors: N
authors: Quillinan
authors: J P
authors: JP
authors: Adelman
authors: P S
authors: PS
authors: Herson
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002545:Brain Ischemia / Q000503:physiopathology* / Q000517:prevention & control; D002120:Calcium Channel Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*
chemical_list: D001562:Benzimidazoles; D002120:Calcium Channel Agonists; C496898:Kcnn2 protein, mouse; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D051640:Small-Conductance Calcium-Activated Potassium Channels; C102635:1-ethyl-2-benzimidazolinone
keywords: cardiac arrest; global cerebral ischemia; hippocampus long-term potentiation; mouse; small conductance Ca2+-activated potassium channels