Simvastatin enhances NMDA receptor GluN2B expression and phosphorylation of GluN2B and GluN2A through increased histone acetylation and Src signaling in hippocampal CA1 neurons

Neuropharmacology. 2016 Aug;107:411-421. doi: 10.1016/j.neuropharm.2016.03.028. Epub 2016 Mar 22.

Abstract

Simvastatin (SV) can improve cognitive deficits in Alzheimer's disease patients and mice. Herein, we report that the administration of SV (20 mg/kg) for 5 days in mice (SV-mice) or the treatment of slices with SV (10 μM) for 4 h (SV-slices) could increase the density of NMDA-evoked inward currents (INMDA) in hippocampal CA1 pyramidal cells, which were blocked by farnesol (FOH) that converts farnesyl pyrophosphate (FPP), but not geranylgeraniol (GGOH) that increases geranylgeranylpyrophosphate (GGPP). Sensitivity of INMDA to ifenprodil in SV-mice or SV-slices was significantly increased. The levels of hippocampal GluN2B and GluN2A or Src phosphorylation in SV-mice or SV-slices were higher than controls, which were sensitive to FOH. The Src inhibitor PP2 could inhibit the SV-enhanced phosphorylation of GluN2B and GluN2A and SV-augmented INMDA, but PI3K inhibitor LY294002 did not. The levels of GluN2B mRNA and protein were elevated in SV-mice, which was abolished by FOH, but not by GGOH or PP2. Furthermore, the histone H3K9 and H3K27 acetylation of GluN2B promoter was increased in SV-mice, which was suppressed by FOH rather than GGOH or PP2. In control mice and slices, the reduction of FPP by farnesyl transferase inhibitor could increase the levels of GluN2B expression, the histone H3K9 and H3K27 acetylation and enhance the phosphorylation of GluN2B, GluN2A and Src. The findings indicate that the administration of SV can enhance GluN2B expression and GluN2B and GluN2A phosphorylation leading to augmentation of NMDAR activity through reducing FPP to increase histone acetylation of GluN2B and Src signaling.

Keywords: Farnesyl-pyrophosphate (FPP); Hippocampus; Histone acetylation of GluN2B; NMDA receptors; Simvastatin; Src.

MeSH terms

  • Acetylation / drug effects
  • Animals
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / metabolism*
  • Gene Expression
  • Histones / metabolism*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Organ Culture Techniques
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • Receptors, N-Methyl-D-Aspartate / biosynthesis*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Simvastatin / pharmacology*
  • src-Family Kinases / metabolism*

Substances

  • Histones
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Simvastatin
  • src-Family Kinases
  • N-methyl D-aspartate receptor subtype 2A