Simvastatin enhances hippocampal long-term potentiation in C57BL/6 mice

R. A. Mans, N. Chowdhury, D. Cao, L. L. Mcmahon, L. Li

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Statins inhibit 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, and they are widely used to control plasma cholesterol levels and prevent cardiovascular disease. However, emerging evidence indicates that the beneficial effects of statins extend to the CNS. Statins have been shown to improve the outcome of stroke and traumatic brain injury, and statin use has been associated with a reduced prevalence of Alzheimer's disease (AD) and dementia. However, prospective studies with statins in AD have produced mixed results. Recently, we reported that simvastatin, a widely used statin in humans, enhances learning and memory in non-transgenic mice as well as in transgenic mice with ADlike pathology on a mixed genetic background. However, the cellular and molecular mechanisms underlying the beneficial effects of simvastatin on learning and memory remain elusive. The present study was undertaken to investigate the effect of acute simvastatin treatment on hippocampal longterm potentiation (LTP), a cellular model of learning and memory, in brain slices from C57BL/6 mice. Our results demonstrate that a prolonged in vitro simvastatin treatment for 2-4 h, but not a short-term 20-min exposure, significantly increases the magnitude of LTP at CA3-CA1 synapses without altering basal synaptic transmission or the paired-pulse facilitation ratio in hippocampal slices. Furthermore, we show that phosphorylation of Akt (protein kinase B) is increased significantly in the CA1 region following 2-hour treatment with simvastatin, and that inhibition of Akt phosphorylation suppresses the simvastatin-induced enhancement of LTP. These findings suggest activation of Akt as a molecular pathway for augmented hippocampal LTP by simvastatin treatment, and implicate enhancement of hippocampal LTP as a potential cellular mechanism underlying the beneficial effects of simvastatin on cognitive function.

Original languageEnglish (US)
Pages (from-to)435-444
Number of pages10
JournalNeuroscience
Volume166
Issue number2
DOIs
StatePublished - Mar 17 2010

Bibliographical note

Funding Information:
We thank Drs. Caroline Smith and Portia McCoy and Hailin Lu for technical support. This work was supported by the National Institutes of Health NIA Award AG-031846 to L. Li, the Neurobiology of Cognition and Cognitive Disorders Training Grant T32 NS-061788 , Neuroscience Blueprint Core Grant NS-57098 , and a grant from an anonymous philanthropic foundation to L. Li. Appendix

Keywords

  • Alzheimer's disease
  • Cognitive function
  • Learning and memory
  • Protein phosphorylation
  • Statins
  • Synaptic plasticity

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