MPEP reduces seizure severity in Fmr-1 KO mice over expressing human Abeta.
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.
Westmark
Cara J
CJ
Department of Pathology & Laboratory Medicine and Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, WI 53705, USA. westmark@wisc.edu
Westmark
Pamela R
PR
Malter
James S
JS
D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000502:physiology*; D005600:Fragile X Syndrome / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058255:Protease Nexins; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000503:physiopathology
D016564:Amyloid beta-Protein Precursor; D014151:Anti-Anxiety Agents; D051860:Fragile X Messenger Ribonucleoprotein 1; D058255:Protease Nexins; D011725:Pyridines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C545487:APP protein, human; C497684:Fmr1 protein, mouse; C121465:6-methyl-2-(phenylethynyl)pyridine