title: Does gene deletion of AMPA GluA1 phenocopy features of schizoaffective disorder?
abstract: Glutamatergic dysfunction is strongly implicated in schizophrenia and mood disorders. GluA1 knockout (KO) mice display schizophrenia- and depression-related abnormalities. Here, we asked whether GluA1 KO show mania-related abnormalities. KO were tested for behavior in approach/avoid conflict tests, responses to repeated forced swim exposure, and locomotor responses under stress and after psychostimulant treatment. The effects of rapid dopamine depletion and treatment with lithium or a GSK-3β inhibitor (SB216763) on KO locomotor hyperactivity were tested. Results showed that KO exhibited novelty- and stress-induced locomotor hyperactivity, reduced forced swim immobility and alterations in approach/avoid conflict tests. Psychostimulant treatment and dopamine depletion exacerbated KO locomotor hyperactivity. Lithium, but not SB216763, treatment normalized KO anxiety-related behavior and partially reversed hyperlocomotor behavior, and also reversed elevated prefrontal cortex levels of phospho-MARCKS and phospho-neuromodulin. Collectively, these findings demonstrate mania-related abnormalities in GluA1 KO and, combined with previous findings, suggest this mutant may provide a novel model of features of schizoaffective disorder.
authors.affiliation: Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852-9411, USA. fitzpj@mail.nih.gov
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fitzgerald
authors.forename: Chris
authors.initials: C
authors.lastname: Barkus
authors.forename: Michael
authors.initials: M
authors.lastname: Feyder
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Wiedholz
authors.forename: Yi-Chyan
authors.initials: YC
authors.lastname: Chen
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Karlsson
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.forename: Carolyn
authors.initials: C
authors.lastname: Graybeal
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
authors.forename: Carlos
authors.initials: C
authors.lastname: Zarate
authors.forename: Judith
authors.initials: J
authors.lastname: Harvey-White
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.forename: Peter
authors.initials: P
authors.lastname: Gass
authors.forename: David
authors.initials: D
authors.lastname: Bannerman
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004195:Disease Models, Animal; D017353:Gene Deletion; D018020:Lithium Compounds / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011618:Psychotic Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism
chemical_list: D018692:Antimanic Agents; D000697:Central Nervous System Stimulants; D018020:Lithium Compounds; D018091:Receptors, AMPA