Abstract
The ramifications of statins on plasma cholesterol and coronary heart disease have been well documented. However, there is increasing evidence that inhibition of the mevalonate pathway may provide independent neuroprotective and procognitive pleiotropic effects, most likely via inhibition of isoprenoids, mainly farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). FPP and GGPP are the major donors of prenyl groups for protein prenylation. Modulation of isoprenoid availability impacts a slew of cellular processes including synaptic plasticity in the hippocampus. Our previous work has demonstrated that simvastatin (SV) administration improves hippocampus-dependent spatial memory, rescuing memory deficits in a mouse model of Alzheimer’s disease. Treatment of hippocampal slices with SV enhances long-term potentiation (LTP), and this effect is dependent on the activation of Akt (protein kinase B). Further studies showed that SV-induced enhancement of hippocampal LTP is driven by depletion of FPP and inhibition of farnesylation. In the present study, we report the functional consequences of exposure to SV at cellular/synaptic and molecular levels. While application of SV has no effect on intrinsic membrane properties of CA1 pyramidal neurons, including hyperpolarization-activated cyclic-nucleotide channel-mediated sag potentials, the afterhyperpolarization (AHP), and excitability, SV application potentiates the N-methyl D-aspartate receptor (NMDAR)-mediated contribution to synaptic transmission. In mouse hippocampal slices and human neuronal cells, SV treatment increases the surface distribution of the GluN2B subunit of the NMDAR without affecting cellular cholesterol content. We conclude that SV-induced enhancement of synaptic plasticity in the hippocampus is likely mediated by augmentation of synaptic NMDAR components that are largely responsible for driving synaptic plasticity in the CA1 region.
Similar content being viewed by others
Abbreviations
- aCSF:
-
Artificial cerebrospinal fluid
- AD:
-
Azheimer’s disease
- AHPs:
-
Afterhyperpolarization potentials
- Akt:
-
Protein kinase B
- AMPA and AMPAR:
-
2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid and AMPA receptor
- fEPSPs:
-
Field excitatory postsynaptic potentials
- FPP:
-
Farnesyl pyrophosphate
- GGPP:
-
Geranylgeranyl pyrophosphate
- GluA1:
-
A subunit of AMPA receptor
- GluN1, GluN2A and GluN2B:
-
Subunits of NMDA receptor
- HCN:
-
Hyperpolarization/cyclic-nucleotide
- HFS:
-
High-frequency stimulation
- HMG-CoA:
-
3-Hydroxy-3-methylglutaryl Coenzyme A
- LTP:
-
Long-term potentiation
- NMDA and NMDAR:
-
N-methyl D-aspartate and NMDA receptor
- SV:
-
Simvastatin
- Veh:
-
Vehicle
References
Abulrob A, Tauskela JS, Mealing G, Brunette E, Faid K, Stanimirovic D (2005) Protection by cholesterol-extracting cyclodextrins: a role for N-methyl-D-aspartate receptor redistribution. J Neurochem 92(6):1477–1486. doi:10.1111/j.1471-4159.2005.03001.x
Akashi K, Kakizaki T, Kamiya H, Fukaya M, Yamasaki M, Abe M, Natsume R, Watanabe M, Sakimura K (2009) NMDA receptor GluN2B (GluR epsilon 2/NR2B) subunit is crucial for channel function, postsynaptic macromolecular organization, and actin cytoskeleton at hippocampal CA3 synapses. J Neurosci 29(35):10869–10882. doi:10.1523/JNEUROSCI.5531-08.2009
Borisova T, Krisanova N, Sivko R, Borysov A (2010) Cholesterol depletion attenuates tonic release but increases the ambient level of glutamate in rat brain synaptosomes. Neurochem Int 56(3):466–478. doi:10.1016/j.neuint.2009.12.006
Bosel J, Gandor F, Harms C, Synowitz M, Harms U, Djoufack PC, Megow D, Dirnagl U, Hortnagl H, Fink KB, Endres M (2005) Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones. J Neurochem 92(6):1386–1398
Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232(4746):34–47
Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, Zhang C, Lu M, Katakowski M, Feldkamp CS, Chopp M (2003) Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 53(6):743–751
Cheng S, Cao D, Hottman DA, Yuan L, Bergo MO, Li L (2013) Farnesyltransferase haplodeficiency reduces neuropathology and rescues cognitive function in a mouse model of Alzheimer disease. J Biol Chem 288(50):35952–35960. doi:10.1074/jbc.M113.503904
Collins R, Armitage J, Parish S, Sleight P, Peto R (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360(9326):7–22
Costa RM, Federov NB, Kogan JH, Murphy GG, Stern J, Ohno M, Kucherlapati R, Jacks T, Silva AJ (2002) Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415(6871):526–530
Endo A (2004) The discovery and development of HMG-CoA reductase inhibitors. 1992. Atheroscler Suppl 5(3):67–80
Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T (2001) Simvastatin strongly reduces levels of Alzheimer’s disease beta—amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci USA 98(10):5856–5861
Ghosh A, Roy A, Matras J, Brahmachari S, Gendelman HE, Pahan K (2009) Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson’s disease. J Neurosci 29(43):13543–13556
Houten SM, Frenkel J, Waterham HR (2003) Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation. Cell Mol Life Sci 60(6):1118–1134. doi:10.1007/s00018-003-2296-4
Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA (2000) Statins and the risk of dementia. Lancet 356(9242):1627–1631
Johnson-Anuna LN, Eckert GP, Keller JH, Igbavboa U, Franke C, Fechner T, Schubert-Zsilavecz M, Karas M, Muller WE, Wood WG (2005) Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Ther 312(2):786–793
Kannel WB, Castelli WP, Gordon T, McNamara PM (1971) Serum cholesterol, lipoproteins, and the risk of coronary heart disease. The Framingham study. Ann Intern Med 74(1):1–12
Kirsch C, Eckert GP, Mueller WE (2003) Statin effects on cholesterol micro-domains in brain plasma membranes. Biochem Pharmacol 65(5):843–856
Krisanova N, Sivko R, Kasatkina L, Borisova T (2012) Neuroprotection by lowering cholesterol: a decrease in membrane cholesterol content reduces transporter-mediated glutamate release from brain nerve terminals. Biochim Biophys Acta 1822 10:1553–1561. doi:10.1016/j.bbadis.2012.06.005
Lapchak PA, Han MK (2010) Simvastatin improves clinical scores in a rabbit multiple infarct ischemic stroke model: synergism with a ROCK inhibitor but not the thrombolytic tissue plasminogen activator. Brain Res 1344:217–225
Li W, Cui Y, Kushner SA, Brown RA, Jentsch JD, Frankland PW, Cannon TD, Silva AJ (2005) The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 15(21):1961–1967
Li L, Cao D, Kim H, Lester R, Fukuchi K (2006) Simvastatin enhances learning and memory independent of amyloid load in mice. Ann Neurol 60(6):729–739
Liao JK (2002) Isoprenoids as mediators of the biological effects of statins. J Clin Invest 110(3):285–288
Manabe T, Aiba A, Yamada A, Ichise T, Sakagami H, Kondo H, Katsuki M (2000) Regulation of long-term potentiation by H-Ras through NMDA receptor phosphorylation. J Neurosci 20(7):2504–2511
Mans RA, Chowdhury N, Cao D, McMahon LL, Li L (2010) Simvastatin enhances hippocampal long-term potentiation in C57BL/6 mice. Neuroscience 166(2):435–444
Mans RA, McMahon LL, Li L (2012) Simvastatin-mediated enhancement of long-term potentiation is driven by farnesyl-pyrophosphate depletion and inhibition of farnesylation. Neuroscience 202:1–9
McTaggart SJ (2006) Isoprenylated proteins. Cell Mol Life Sci 63(3):255–267
Ponce J, de la Ossa NP, Hurtado O, Millan M, Arenillas JF, Davalos A, Gasull T (2008) Simvastatin reduces the association of NMDA receptors to lipid rafts: a cholesterol-mediated effect in neuroprotection. Stroke 39(4):1269–1275. doi:10.1161/STROKEAHA.107.498923
Prospective Studies C, Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R, Collins R (2007) Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 370(9602):1829–1839. doi:10.1016/S0140-6736(07)61778-4
Ramirez C, Tercero I, Pineda A, Burgos JS (2011) Simvastatin is the statin that most efficiently protects against kainate-induced excitotoxicity and memory impairment. J Alzheimers Dis 24(1):161–174
Sah P, Hestrin S, Nicoll RA (1989) Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons. Science 246(4931):815–818
Shepardson NE, Shankar GM, Selkoe DJ (2010) Cholesterol level and statin use in Alzheimer disease: II. review of human trials and recommendations. Arch Neurol 68(11):1385–1392
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG (2002) Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 360(9346):1623–1630
Simons M, Schwarzler F, Lutjohann D, von Bergmann K, Beyreuther K, Dichgans J, Wormstall H, Hartmann T, Schulz JB (2002) Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol 52(3):346–350
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8(8):1051–1058
Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C (2005) Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol 62(5):753–757
Suvarna N, Borgland SL, Wang J, Phamluong K, Auberson YP, Bonci A, Ron D (2005) Ethanol alters trafficking and functional N-methyl-D-aspartate receptor NR2 subunit ratio via H-Ras. J Biol Chem 280(36):31450–31459. doi:10.1074/jbc.M504120200
Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ (1999) Genetic enhancement of learning and memory in mice. Nature 401(6748):63–69. doi:10.1038/43432
Vaughan CJ (2003) Prevention of stroke and dementia with statins: effects beyond lipid lowering. Am J Cardiol 91(4A):23B–29B
Vedder LC, Smith CC, Flannigan AE, McMahon LL (2013) Estradiol-induced increase in novel object recognition requires hippocampal NR2B-containing NMDA receptors. Hippocampus 23(1):108–115. doi:10.1002/hipo.22068
Wang Q, Zengin A, Deng C, Li Y, Newell KA, Yang GY, Lu Y, Wilder-Smith EP, Zhao H, Huang XF (2009) High dose of simvastatin induces hyperlocomotive and anxiolytic-like activities: the association with the up-regulation of NMDA receptor binding in the rat brain. Exp Neurol 216(1):132–138
Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding JD, Feliciano C, Chen M, Adams JP, Luo J, Dudek SM, Weinberg RJ, Calakos N, Wetsel WC, Feng G (2007) Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448(7156):894–900. doi:10.1038/nature06104
Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3- methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 57(10):1439–1443
Wu H, Lu D, Jiang H, Xiong Y, Qu C, Li B, Mahmood A, Zhou D, Chopp M (2008) Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3 K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. J Neurotrauma 25(2):130–139
Zacco A, Togo J, Spence K, Ellis A, Lloyd D, Furlong S, Piser T (2003) 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity. J Neurosci 23(35):11104–11111
Acknowledgments
The authors would like to thank Dr. Robert A. Mans (University of Alabama at Birmingham, AL, USA) for his technical assistance and helpful discussions. This study was supported in part by grants from the National Institutes of Health (AG031846), the Alzheimer’s Drug Discovery Foundation (#20131002), the Alzheimer’s Association (IIRG-09-131791), the BrightFocus Foundation (formerly the American Health Assistance Foundation) (A2010328), and the College of Pharmacy (Engebretson/Bighley Drug Design and Development Program), and the Academic Health Center of the University of Minnesota to LL.
Conflict of interest
The authors declare that there are no conflicts of interest.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Parent, MA.L.T., Hottman, D.A., Cheng, S. et al. Simvastatin Treatment Enhances NMDAR-Mediated Synaptic Transmission by Upregulating the Surface Distribution of the GluN2B Subunit. Cell Mol Neurobiol 34, 693–705 (2014). https://doi.org/10.1007/s10571-014-0051-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-014-0051-z