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

Abstract

Statins inhibit 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA), 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 central nervous system. 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 AD-like 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 hrs, 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. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 March 17. Statins inhibit the rate-limiting reaction in the mevalonate biosynthetic pathway for cholesterol, which entails conversion of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) to mevalonate via HMG-CoA reductase (Brown and Goldstein, 1986). Inhibiting this reaction not only reduces de novo cholesterol synthesis, but also prevents the formation of isoprenoid intermediates, such as farnesyl-pyrophosphate (PP) and geranylgeranyl-PP, which serve as lipid attachments for variou...

LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery

“…Strong depression of basal synaptic transmission and LTP impairment has been observed upon cholesterol reduction with cyclodextrin (Frank et al, 2008). In contrast, LTP enhancement and no effect on basal transmission were reported with a statin inhibitor of cholesterol biosynthesis (Mans et al, 2010). However, the opposite effect (LTP impairment) was observed using a different statin (Kotti et al, 2006).…”

Hesperidin, a citrus flavonoid, protects against l -methionine-induced hyperhomocysteinemia by abrogation of oxidative stress, endothelial dysfunction and neurotoxicity in Wistar rats

“…These observations are in concurrence with reports from the present study and another laboratory ) and the dose-dependent effect is seen with HSP treatment. The improvement in spatial memory as measured by the two different maze tasks is dependent on hippocampus-mediated learning and memory, which is related to the NMDA receptor/Ca 2 þ influx signalling pathway (Obeid & Herrmann 2006).Recent reports have revealed that flavonoids and other small molecules or drugs affect long-term potentiation and consequently, memory and cognitive performance through their interactions with these signalling pathways (Maher 2008;Mans et al 2010).…”

Age-Dependent Rescue by Simvastatin of Alzheimer's Disease Cerebrovascular and Memory Deficits

“…Particularly, chronic simvastatin treatment increased brain levels of total and phosphorylated Akt (P-Akt) in WT mice with enhanced learning and memory performance (Li et al, 2006). In hippocampal slices from WT mice, prolonged simvastatin treatment increased P-Akt in the CA1 area concomitantly with improved LTP at CA3-CA1 synapses, an effect suppressed by inhibition of Akt phosphorylation (Mans et al, 2010). Together, these findings support that simvastatin rescued memory in adult APP mice by restoring the ability of hippocampal CA1 neurons to respond to synaptic input, possibly by restoring the PI3K/Akt 3 P-CREB 3 Egr-1/cFos signaling cascade that is crucial for spatial memory.…”