title: Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome.
abstract: BACKGROUND
  Abnormal dendritic spine morphology is a significant neuroanatomical defect in fragile X mental retardation. It has been suggested that overactive group 1 metabotropic glutamate receptor (mGlu) signaling is associated with the spine dysmorphology occurring in fragile X syndrome (FXS). Thus, group 1 mGlu became a new therapeutic target for the treatment of FXS.
  
  
  OBJECTIVE
  The purpose of this study was to identify the effect of inhibition of mGlu signaling in FXS.
  
  
  METHODS
  We observed the changes in dendritic spines after pharmacological modulation of mGlu signaling in an Fmr1 knockout (KO) mouse model.
  
  
  RESULTS
  The activation of group 1 mGlu resulted in elongation of dendritic spines in the cultured neurons derived from Fmr1 KO mice and wild-type (WT) mice. Antagonism of group 1 mGlu reduced the average spine length of Fmr1 KO neurons. Furthermore, systemic administration of the selective group 1 mGlu5 antagonist 2-methyl-6-phenylethynyl pyridine (MPEP) reduced the average spine length and density in the cortical neurons of Fmr1 KO mice at developmental age. For the adult mice, MPEP administration was less effective for the restoration of spine length. The percentage of immature spines showed a similar reduction in parallel to the changes of spine length. Temporary MPEP intervention with single-dose treatment did not show any effect.
  
  
  CONCLUSIONS
  These results show that MPEP administration could partially rescue the morphological deficits of dendritic spines in Fmr1 KO mice at developmental age.
authors.affiliation: Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Chang-gang-dong Road 250, Guangzhou 510260, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Fan
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Sun
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Den
authors.forename: Mei-Mei
authors.initials: MM
authors.lastname: Gao
authors.forename: Sheng-Qiang
authors.initials: SQ
authors.lastname: Chen
authors.forename: Qi-Hua
authors.initials: QH
authors.lastname: Zhao
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Yi
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001578:Benzopyrans / Q000494:pharmacology; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects* / Q000473:pathology*; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D006624:Hippocampus / Q000473:pathology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000473:pathology* / Q000648:ultrastructure; D011725:Pyridines / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016622:Silver Staining / Q000379:methods
chemical_list: D001578:Benzopyrans; D051860:Fragile X Messenger Ribonucleoprotein 1; D008734:Methoxyhydroxyphenylglycol; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C442478:N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide; C104077:metabotropic glutamate receptor type 1; C121465:6-methyl-2-(phenylethynyl)pyridine; C010117:3,4-dihydroxyphenylglycol