Correction of fragile X syndrome in mice.
Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.
Dölen
Gül
G
Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Osterweil
Emily
E
Rao
B S Shankaranarayana
BS
Smith
Gordon B
GB
Auerbach
Benjamin D
BD
Chattarji
Sumantra
S
Bear
Mark F
MF
D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D007839:Functional Laterality / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D006579:Heterozygote; D007858:Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015999:Multivariate Analysis; D009473:Neuronal Plasticity; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency / Q000235:genetics*; D012640:Seizures / Q000209:etiology; D014793:Visual Cortex / Q000503:physiopathology
D051860:Fragile X Messenger Ribonucleoprotein 1; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse