title: The effect of an mGluR5 inhibitor on procedural memory and avoidance discrimination impairments in Fmr1 KO mice.
abstract: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Patients with FXS do not only suffer from cognitive problems, but also from abnormalities/deficits in procedural memory formation. It has been proposed that a lack of fragile X mental retardation protein (FMRP) leads to altered long-term plasticity by deregulation of various translational processes at the synapses, and that part of these impairments might be rescued by the inhibition of type I metabotropic glutamate receptors (mGluRs). We recently developed the Erasmus Ladder, which allows us to test, without any invasive approaches, simultaneously, both procedural memory formation and avoidance behavior during unperturbed and perturbed locomotion in mice. Here, we investigated the impact of a potent and selective mGluR5 inhibitor (Fenobam) on the behavior of Fmr1 KO mice during the Erasmus Ladder task. Fmr1 KO mice showed deficits in associative motor learning as well as avoidance behavior, both of which were rescued by intraperitoneal administration of Fenobam. While the Fmr1 KO mice did benefit from the treatment, control littermates suffered from a significant negative side effect in that their motor learning skills, but not their avoidance behavior, were significantly affected. On the basis of these studies in the FXS animal model, it may be worthwhile to investigate the effects of mGluR inhibitors on both the cognitive functions and procedural skills in FXS patients. However, the use of mGluR inhibitors appears to be strongly contraindicated in healthy controls or non-FXS patients with intellectual disability.
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, Rotterdam Netherlands.
authors.forename: M F
authors.initials: MF
authors.lastname: Vinueza Veloz
authors.forename: R A M
authors.initials: RA
authors.lastname: Buijsen
authors.forename: R
authors.initials: R
authors.lastname: Willemsen
authors.forename: A
authors.initials: A
authors.lastname: Cupido
authors.forename: L W J
authors.initials: LW
authors.lastname: Bosman
authors.forename: S K E
authors.initials: SK
authors.lastname: Koekkoek
authors.forename: J W
authors.initials: JW
authors.lastname: Potters
authors.forename: B A
authors.initials: BA
authors.lastname: Oostra
authors.forename: C I
authors.initials: CI
authors.lastname: De Zeeuw
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000150:complications / Q000503:physiopathology* / Q000523:psychology; D007093:Imidazoles / Q000633:toxicity; D008569:Memory Disorders / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D007093:Imidazoles; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C578936:Grm5 protein, mouse; C032794:fenobam