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. 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.

EEG power as a biomarker to predict the outcome after cardiac arrest and cardiopulmonary resuscitation induced global ischemia

“…Interestingly, suppression of background EEG and increase in spike activity occurred in both the cortices and in the hippocampus, however, the seizure activity was restricted only to the hippocampus. It has been shown that these mice have hippocampal cell loss and impaired synaptic plasticity that may have been the result of ischemia-induced excessive excitation [7,13,14]. Earlier studies have also shown that the mouse model used in the current study replicates brain injury patterns and neurological deficits of human disease condition [7,15].…”

Neuropathophysiology of Brain Injury

“…35–37 The loss of LTP is sustained for at least 1 month, which is well beyond the time of neuronal cell death. 38, 39 This finding implies that, in addition to cell death, these forms of brain injury can produce long-lasting changes in synaptic function of surviving neurons, which likely contributes to a lack of recovery of function. The mechanisms contributing to LTP deficits remain to be elucidated, but likely candidates include excitatory/inhibitory imbalance, alterations of intracellular signaling, and prolonged neuroinflammation.…”

Sirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels

“…We have previously demonstrated that CA/CPR-induced functional deficits are associated with long lasting impairments in hippocampal synaptic plasticity (Allen et al, 2011; Orfila et al, 2014). Therefore, in order to assess the functional benefit of AGK2 neuroprotection, male mice subjected to CA/CPR were administered AGK2 at 30 min after CA/CPR and hippocampal synaptic function was assessed in acute slices at 7 or 30 days after CA/CPR.…”

“…Extracellular recording of field excitatory postsynaptic potentials (fEPSPs) was performed in acute hippocampal sections as previously described (Orfila et al, 2014). One week after CA/CPR or sham surgery mice were deeply anesthetized with isoflurane (5%) and transcardially perfused with ice-cold artificial cerebral spinal fluid (ACSF).…”