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

Metabotropic glutamate receptor 5 (mGluR₅) 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 Aβ on Fragile X syndrome (FXS) phenotypes, we created a novel mouse model (FRAXAD) that over-expresses human APP_Swe/Aβ in an fmr-1 KO background. Herein, we assess (1) human APP_Swe and Aβ levels as a function of age in FRAXAD mice, and (2) seizure susceptibility to pentylenetetrazol (PTZ) after mGluR₅ blockade. PTZ-induced seizure severity is decreased in FRAXAD mice pre-treated with the mGluR₅ antagonist MPEP. These data suggest that Aβ 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.