MPEP reduces seizure severity in Fmr-1 KO mice over expressing human Abeta

Int J Clin Exp Pathol. 2009 Oct 10;3(1):56-68.

Abstract

Metabotropic glutamate receptor 5 (mGluR(5)) regulates the translation of amyloid precursor protein (APP) mRNA. Under resting conditions, mRNA is bound to and translationally repressed by the fragile X mental retardation protein (FMRP). Upon group 1 mGluR activation, FMRP dissociates from the mRNA and translation ensues. APP levels are elevated in the dendrites of primary neuronal cultures as well as in synaptoneurosomes (SN) prepared from embryonic and juvenile fmr-1 knockout (KO) mice, respectively. In order to study the effects of APP and its proteolytic product Abeta on Fragile X syndrome (FXS) phenotypes, we created a novel mouse model (FRAXAD) that over-expresses human APPSwe/Abeta in an fmr-1 KO background. Herein, we assess (1) human APP(Swe) and Abeta levels as a function of age in FRAXAD mice, and (2) seizure susceptibility to pentylenetetrazol (PTZ) after mGluR(5) blockade. PTZ-induced seizure severity is decreased in FRAXAD mice pre-treated with the mGluR(5) antagonist MPEP. These data suggest that Abeta contributes to seizure incidence and may be an appropriate therapeutic target to lessen seizure pathology in FXS, Alzheimer's disease (AD) and Down syndrome (DS) patients.

Keywords: APP; FMRP; FRAXAD; PTZ; Tg2576; seizure; β-amyloid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / physiology*
  • Fragile X Syndrome / complications
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / physiopathology
  • Gene Expression
  • Gene Silencing
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protease Nexins
  • Pyridines / pharmacology*
  • RNA, Messenger / genetics
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Seizures / drug therapy*
  • Seizures / etiology
  • Seizures / genetics
  • Seizures / physiopathology

Substances

  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Anti-Anxiety Agents
  • Fmr1 protein, mouse
  • Protease Nexins
  • Pyridines
  • RNA, Messenger
  • Receptors, Cell Surface
  • Fragile X Mental Retardation Protein
  • 6-methyl-2-(phenylethynyl)pyridine