title: Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice.
abstract: Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, but a crucial unanswered question is whether pharmacological mGlu5 inhibition is able to reverse an already established FXS phenotype in mammals. Here we have used the novel, potent, and selective mGlu5 inhibitor CTEP to address this issue in the Fmr1 knockout mouse. Acute CTEP treatment corrects elevated hippocampal long-term depression, protein synthesis, and audiogenic seizures. Chronic treatment that inhibits mGlu5 within a receptor occupancy range of 81% ± 4% rescues cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrects macroorchidism. This study shows that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype. It is of great interest how these findings may translate into ongoing clinical research testing mGlu5 inhibitors in FXS patients.
authors.affiliation: Discovery Neuroscience, Pharmaceuticals Division, F. Hoffmann-La Roche, CH-4070 Basel, Switzerland.
authors.forename: Aubin
authors.initials: A
authors.lastname: Michalon
authors.forename: Michael
authors.initials: M
authors.lastname: Sidorov
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ballard
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: Will
authors.initials: W
authors.lastname: Spooren
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
authors.forename: Georg
authors.initials: G
authors.lastname: Jaeschke
authors.forename: Mark F
authors.initials: MF
authors.lastname: Bear
authors.forename: Lothar
authors.initials: L
authors.lastname: Lindemann
mesh_terms: D000367:Age Factors; D000818:Animals; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011725:Pyridines / Q000627:therapeutic use*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D007093:Imidazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C569289:2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine; C497684:Fmr1 protein, mouse