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Simvastatin Treatment Enhances NMDAR-Mediated Synaptic Transmission by Upregulating the Surface Distribution of the GluN2B Subunit

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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.

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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

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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.

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The authors declare that there are no conflicts of interest.

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Correspondence to Li-Lian Yuan or Ling Li.

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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

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