title: 5-HT(6)  receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia.
abstract: Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5-HT(6)  receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5-HT(6)  receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR. Further, 5-HT(6)  receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5-HT(6)  agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post-weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5-HT(6)  antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5-HT(6)  receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control.
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Meffre
authors.forename: Séverine
authors.initials: S
authors.lastname: Chaumont-Dubel
authors.forename: Clotilde
authors.initials: C
authors.lastname: Mannoury la Cour
authors.forename: Florence
authors.initials: F
authors.lastname: Loiseau
authors.forename: David J G
authors.initials: DJ
authors.lastname: Watson
authors.forename: Anne
authors.initials: A
authors.lastname: Dekeyne
authors.forename: Martial
authors.initials: M
authors.lastname: Séveno
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rivet
authors.forename: Florence
authors.initials: F
authors.lastname: Gaven
authors.forename: Paul
authors.initials: P
authors.lastname: Déléris
authors.forename: Denis
authors.initials: D
authors.lastname: Hervé
authors.forename: Kevin C F
authors.initials: KC
authors.lastname: Fone
authors.forename: Joël
authors.initials: J
authors.lastname: Bockaert
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.forename: Philippe
authors.initials: P
authors.lastname: Marin
mesh_terms: D000818:Animals; D002460:Cell Line; D003071:Cognition; D006801:Humans; D008297:Male; D051379:Mice; D025941:Protein Interaction Mapping; D020543:Proteome / Q000032:analysis; D040901:Proteomics / Q000379:methods; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D012559:Schizophrenia / Q000503:physiopathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D020543:Proteome; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases