?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.title=Suppression+of+two+major+Fragile+X+Syndrome+mouse+model+phenotypes+by+the+mGluR5+antagonist+MPEP&rft.creator=Bauchwitz%2C+Dr.+Robert&rft.subject=Neuropharmacology&rft.description=Fragile+X+Syndrome+is+the+most+common+form+of+inherited+mental+retardation+worldwide.+A+Fragile+X+mouse+model%2C+fmr1%2C+with+a+disruption+in+the+X-linked+Fmr1+gene%2C+has+three+substantial+deficits+observed+in+several+strains%3A+(1)+sensitivity+to+audiogenic+seizures+(AGS)%2C+(2)+tendency+to+spend+significantly+more+time+in+the+center+of+an+open+field%2C+and+(3)+enlarged+testes.+Alterations+in+metabotropic+glutamate+receptor+group+I+signaling+were+previously+identified+in+the+fmr1+tm1Cgr+mouse.+In+this+study%2C+we+examined+the+effect+of+MPEP%2C+an+antagonist+of+the+group+I+metabotropic+glutamate+receptor+mGluR5%2C+on+audiogenic+seizures+and+open+field+activity+of+fmr1+tm1Cgr+mice.+Genetic+analysis+revealed+synergistic+reactions+between+fmr1tm1Cgr+and+inbred+AGS+alleles.+In+addition%2C+AGS+sensitivity+due+to+the+fmr1+tm1Cgr+allele+was+restricted+during+development.+Examination+of+phenotypes+combining+mGluR5+inhibition+and+Fmr1+mutation+indicated+that+absence+of+FMRP+may+affect+mGluR5+signaling+through+indirect+as+well+as+direct+pathways.+All+strains+of+fmr1+tm1Cgr+mice+tested+(FVB%2FNJ%2C+C57BL%2F6J%2C+and+an+F1+hybrid+of+the+two)+had+a+more+excitable+AGS+pathway+than+wild-type%2C+and+consequently+required+more+MPEP+to+achieve+seizure+suppression.+At+high+doses+of+mGluR5+antagonists%2C+a+Fragile+X+specific+tolerance+(loss+of+drug+activity)+was+observed.+The+tolerance+effect+could+be+overcome+by+a+further+increase+in+drug+dose.+In+open+field+tests%2C+MPEP+reduced+fmr1+tm1Cgr+center+field+behavior+to+one+indistinguishable+from+wild-type.+Therefore%2C+mGluR5+antagonists+were+able+to+rescue+two+of+the+major+phenotypes+of+the+FX+mouse.+Modulation+of+mGluR5+signaling+may+allow+amelioration+of+symptoms+of+Fragile+X+Syndrome.+&rft.publisher=Elsevier&rft.date=2005-07-27&rft.type=Journal+(Paginated)&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.identifier=http%3A%2F%2Fcogprints.org%2F6538%2F1%2FYan2005Neuropharm_in-press_with_Supplementary_Material_file.pdf&rft.identifier=++Bauchwitz%2C+Dr.+Robert++(2005)+Suppression+of+two+major+Fragile+X+Syndrome+mouse+model+phenotypes+by+the+mGluR5+antagonist+MPEP.++%5BJournal+(Paginated)%5D+++++&rft.relation=http%3A%2F%2Fcogprints.org%2F6538%2F