Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice.
Lack of fragile X mental retardation protein (FMRP) causes Fragile X Syndrome, the most common form of inherited mental retardation. FMRP is an RNA-binding protein and is a component of messenger ribonucleoprotein complexes, associated with brain polyribosomes, including dendritic polysomes. FMRP is therefore thought to be involved in translational control of specific mRNAs at synaptic sites. In mice lacking FMRP, protein synthesis-dependent synaptic plasticity is altered and structural malformations of dendritic protrusions occur. One hypothesized cause of the disease mechanism is based on exaggerated group I mGluR receptor activation. In this study, we examined the effect of the mGluR5 antagonist MPEP on Fragile X related behavior in Fmr1 KO mice. Our results demonstrate a clear defect in prepulse inhibition of startle in Fmr1 KO mice, that could be rescued by MPEP. Moreover, we show for the first time a structural rescue of Fragile X related protrusion morphology with two independent mGluR5 antagonists.
Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
Femke M S
FM
de Vrij
Josien
J
Levenga
Herma C
HC
van der Linde
Sebastiaan K
SK
Koekkoek
Chris I
CI
De Zeeuw
David L
DL
Nelson
Ben A
BA
Oostra
Rob
R
Willemsen
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D013216:Reflex, Startle / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D007093:Imidazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C578936:Grm5 protein, mouse; C032794:fenobam; C121465:6-methyl-2-(phenylethynyl)pyridine