title: Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant.
abstract: Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism. The disease is a result of lack of expression of the fragile X mental retardation protein. Brain tissues of patients with FXS and mice with FMRP deficiency have shown an abnormal dendritic spine phenotype. We investigated the dendritic spine length and density of hippocampal CA1 pyramidal neurons in 2-, 10-, and 25-week-old Fmr1 knockout (KO). Next, we studied the effects of long-term treatment with an mGluR5 antagonist, AFQ056/Mavoglurant, on the spine phenotype in adult Fmr1 KO mice. We observed alterations in the spine phenotype during development, with a decreased spine length in 2-week-old Fmr1 KO mice compared with age-match wild-type littermates, but with increased spine length in Fmr1 KO mice compared with 10- and 25-week-old wild-type controls. No difference was found in spine density at any age. We report a rescue of the abnormal spine length in adult Fmr1 KO mice after a long-term treatment with AFQ056/Mavoglurant. This finding suggests that long-term treatment at later stage is sufficient to reverse the structural spine abnormalities and represents a starting point for future studies aimed at improving treatments for FXS.
authors.affiliation: CBG-Department of Clinical Genetics, Erasmus Medical Centre, Dr. Molewaterplein 55, 3015GE, Rotterdam, The Netherlands.
authors.forename: Andreea S
authors.initials: AS
authors.lastname: Pop
authors.forename: Josien
authors.initials: J
authors.lastname: Levenga
authors.forename: Celine E F
authors.initials: CE
authors.lastname: de Esch
authors.forename: Ronald A M
authors.initials: RA
authors.lastname: Buijsen
authors.forename: Ingeborg M
authors.initials: IM
authors.lastname: Nieuwenhuizen
authors.forename: Tracy
authors.initials: T
authors.lastname: Li
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D049229:Dendritic Spines / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010641:Phenotype; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D007211:Indoles; D064529:Receptor, Metabotropic Glutamate 5; C497684:Fmr1 protein, mouse; C578936:Grm5 protein, mouse; C581397:mavoglurant