Underlying Mechanisms Of Preconditioning Against Stroke: Lack Of Ischemic Neuroprotectant Sirt1 Increases Long-Term Potentiation Induction In Mice.

Sirt1 has been implicated to play a major role in ischemic preconditioning (IPC)—a phenomenon whereby a sublethal episode of ischemia induces tolerance to a subsequent prolonged ischemic insult, such as stroke. Both IPC and pharmacological mimetics (i.e. resveratrol) upregulate Sirt1 activity and expression. Since Sirt1 is thought to regulate the expression of proteins involved in synaptic plasticity, neuroprotection afforded by Sirt1 may be explained by changes in these processes. For this reason, we investigated the effects of Sirt1 deficiency on long-term potentiation (LTP). Using inducible, neuronal-specific Sirt1 knockout mice, acute brain slices were prepared and extracellular field recordings were taken in the CA1 region of the hippocampus. Sirt1 deficiency significantly increased LTP induction (2.08 ± 0.065 fold change relative to a 1.46 ± 0.054 change in wild-type mice; n = 10-11, p = 0.022), suggesting Sirt1 may function to repress the transcription of genes associated with LTP. Paired-pulse facilitation was also significantly increased, where neuronal Sirt1 knockout mice had a 2.10 ± 0.047 fold increase in the paired-pulse response after LTP compared to that of the wild-type control (1.60 ± 0.040; n = 10-11, p = 0.001). These changes were indicative of presynaptic involvement. To test whether similar changes in plasticity occur during the late phase of preconditioning, wild-type mice were treated with resveratrol or a vehicle control and subjected to electrophysiological recordings ex vivo 48 hours later. However, no differences in LTP induction or paired-pulse facilitation were observed. Thus, it is unclear whether protection mediated by resveratrol preconditioning involves changes in synaptic plasticity. Since Sirt1 is capable of deacetylating many histone and non-histone proteins, its effects on transcription and gene expression may vary depending on its activity and period of activation. It is probable that during the extended window of ischemic tolerance, Sirt1 may exert different effects than that of the early or classical late phase. Thus, future studies investigating the effects of Sirt1 on plasticity across different time windows of IPC may shed light on new, more direct targets that can mimic or facilitate preconditioning.