title: Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test.
abstract: Fragile X syndrome is the most common monogenetic form of intellectual disability and autism. Although the Fmr1 knockout mouse model recapitulates many aspects of the human FXS condition, the establishment of robust social behavioural phenotypes suitable for drug screening has been difficult. Here, we describe a novel social behavioural paradigm, the Automated Tube Test (ATT), for which Fmr1 knockout mice demonstrate a highly reliable and robust phenotype. Fmr1 KO mice show highly dominant behaviour over wild-type littermates in the ATT. Consistent with previous findings, we observed a highly significant, albeit partial, rescue of the altered social behaviour of Fmr1 knockout mice in the ATT, using genetic (mGluR5 deletion) or pharmacological inhibition (mGluR5 antagonist) of mGluR5 signalling independently. Together, our results validate the Automated Tube Test as a robust outcome measure for social behaviour in preclinical research for FXS, and confirm the pathophysiological relevance of mGluR5 signalling. Moreover, our findings highlight the strategy of initiating pharmacological intervention in adulthood as holding significant clinical potential.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: C E F
authors.initials: CE
authors.lastname: de Esch
authors.affiliation: Department of Psychiatry, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: W E
authors.initials: WE
authors.lastname: van den Berg
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: R A M
authors.initials: RA
authors.lastname: Buijsen
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: I A
authors.initials: IA
authors.lastname: Jaafar
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: I M
authors.initials: IM
authors.lastname: Nieuwenhuizen-Bakker
authors.affiliation: Novartis Institutes for BioMedical Research Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Gasparini
authors.affiliation: Department of Psychiatry, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: S A
authors.initials: SA
authors.lastname: Kushner
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands. Electronic address: r.willemsen@erasmusmc.nl.
authors.forename: R
authors.initials: R
authors.lastname: Willemsen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology*; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation; D011581:Psychological Tests; D011619:Psychotropic Drugs / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000172:deficiency*; D012919:Social Behavior; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D007211:Indoles; D011619:Psychotropic Drugs; D064529:Receptor, Metabotropic Glutamate 5; C497684:Fmr1 protein, mouse; C578936:Grm5 protein, mouse; C581397:mavoglurant
keywords: ERK; Fragile X; Glutamate receptor; Social behaviour; Tube