Does gene deletion of AMPA GluA1 phenocopy features of schizoaffective disorder?
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.
Fitzgerald
Paul J
PJ
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
Barkus
Chris
C
Feyder
Michael
M
Wiedholz
Lisa M
LM
Chen
Yi-Chyan
YC
Karlsson
Rose-Marie
RM
Machado-Vieira
Rodrigo
R
Graybeal
Carolyn
C
Sharp
Trevor
T
Zarate
Carlos
C
Harvey-White
Judith
J
Du
Jing
J
Sprengel
Rolf
R
Gass
Peter
P
Bannerman
David
D
Holmes
Andrew
A
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
D018692:Antimanic Agents; D000697:Central Nervous System Stimulants; D018020:Lithium Compounds; D018091:Receptors, AMPA