title: Excessive novelty-induced c-Fos expression and altered neurogenesis in the hippocampus of GluA1 knockout mice.
abstract: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit-deficient (GluA1-/-) mice display novelty-induced hyperactivity, cognitive and social defects and may model psychiatric disorders, such as schizophrenia and depression/mania. We used c-Fos expression in GluA1-/- mice to identify brain regions responsible for novelty-induced hyperlocomotion. Exposure to a novel cage for 2 h significantly increased c-Fos expression in many brain regions in both wild-type and knockout mice. Interestingly, the clearest genotype effect was observed in the hippocampus and its main input region, the entorhinal cortex, where the novelty-induced c-Fos expression was more strongly enhanced in GluA1-/- mice. Their novelty-induced hyperlocomotion partly depended on the activity of AMPA receptors, as it was diminished by the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulphonamide (NBQX) and unaffected by the AMPA receptor potentiator 2,3-dihydro-1,4-benzodioxin-6-yl-1-piperidinylmethanone (CX546). The hyperlocomotion of GluA1-/- mice was normalised to the level of wild-type mice within 5-6 h, after which their locomotion followed normal circadian rhythm and was not affected by acute or chronic treatments with the selective serotonin reuptake inhibitor escitalopram. We propose that hippocampal dysfunction, as evidenced by the excessive c-Fos response to novelty, is the major contributor to novelty-induced hyperlocomotion in GluA1-/- mice. Hippocampal dysfunction was also indicated by changes in proliferation and survival of adult-born dentate gyrus cells in the knockout mice. These results suggest focusing on the functions of hippocampal formation, such as novelty detection, when using the GluA1-/- mouse line as a model for neuropsychiatric and cognitive disorders.
authors.affiliation: Institute of Biomedicine/Pharmacology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Procaccini
authors.forename: Teemu
authors.initials: T
authors.lastname: Aitta-aho
authors.forename: Külli
authors.initials: K
authors.lastname: Jaako-Movits
authors.forename: Alexander
authors.initials: A
authors.lastname: Zharkovsky
authors.forename: Anne
authors.initials: A
authors.lastname: Panhelainen
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.forename: Anni-Maija
authors.initials: AM
authors.lastname: Linden
authors.forename: Esa R
authors.initials: ER
authors.lastname: Korpi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015283:Citalopram / Q000378:metabolism; D005106:Exploratory Behavior / Q000502:physiology*; D005260:Female; D005838:Genotype; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D009422:Nervous System Diseases / Q000503:physiopathology; D055495:Neurogenesis / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D015283:Citalopram; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D017367:Selective Serotonin Reuptake Inhibitors