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Published on: May 16, 2019
MPEP reduces seizure severity in Fmr-1 KO mice over expressing human Abeta
Cara J Westmark1, Pamela R Westmark, James S Malter
1Department of Pathology & Laboratory Medicine and Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, WI 53705, USA. westmark@wisc.edu
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.
Insights
Amyloid precursor protein (APP) and its product, amyloid beta (Abeta), contribute to seizures in Fragile X syndrome (FXS). Blocking metabotropic glutamate receptor 5 (mGluR5) reduced seizure severity in a novel mouse model, suggesting Abeta as a therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Metabotropic glutamate receptor 5 (mGluR5) controls amyloid precursor protein (APP) mRNA translation.
- Fragile X mental retardation protein (FMRP) normally represses APP mRNA translation.
- Elevated APP levels are observed in Fragile X knockout mouse models.
Purpose of the Study:
- To investigate the impact of APP and Abeta on Fragile X syndrome (FXS) phenotypes.
- To create and characterize a novel mouse model (FRAXAD) overexpressing human APPSwe/Abeta in an FMR-1 knockout background.
- To assess age-dependent APP/Abeta levels and seizure susceptibility in FRAXAD mice.
Main Methods:
- Developed a novel FRAXAD mouse model (FMR-1 KO background with human APPSwe/Abeta overexpression).
- Quantified human APP and Abeta levels across different ages in FRAXAD mice.
- Evaluated seizure susceptibility using pentylenetetrazol (PTZ) challenge, with and without mGluR5 blockade (MPEP).
Main Results:
- FRAXAD mice exhibited elevated APP and Abeta levels.
- PTZ-induced seizure severity was significantly reduced in FRAXAD mice pre-treated with the mGluR5 antagonist MPEP.
- These findings link Abeta accumulation to increased seizure incidence.
Conclusions:
- Abeta contributes to seizure pathology in the context of FXS.
- Targeting mGluR5 or Abeta may offer therapeutic benefits for seizure management in FXS, Alzheimer's disease (AD), and Down syndrome (DS).
