title: Reversal of novelty-induced hyperlocomotion and hippocampal c-Fos expression in GluA1 knockout male mice by the mGluR2/3 agonist LY354740.
abstract: Dysfunctional glutamatergic neurotransmission has been implicated in schizophrenia and mood disorders. As a putative model for these disorders, a mouse line lacking the GluA1 subunit (GluA1-KO) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor displays a robust novelty-induced hyperlocomotion associated with excessive neuronal activation in the hippocampus. Agonists of metabotropic glutamate 2/3 receptors (mGluR2/3) inhibit glutamate release in various brain regions and they have been shown to inhibit neuronal activation in the hippocampus. Here, we tested a hypothesis that novelty-induced hyperlocomotion in the GluA1-KO mice is mediated via excessive hippocampal neuronal activation by analyzing whether an mGluR2/3 agonist inhibits this phenotypic feature. GluA1-KO mice and littermate wildtype (WT) controls were administered with (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) (15 mg/kg, i.p.) 30 min before a 2-h exposure to novel arenas after which c-Fos immunopositive cells were analyzed in the hippocampus. LY354740 (15 mg/kg) decreased hyperactivity in male GluA1-KO mice, with only a minimal effect in WT controls. This was observed in two cohorts of animals, one naïve to handling and injections, another pre-handled and accustomed to injections. LY354740 (15 mg/kg) also reduced the excessive c-Fos expression in the dorsal hippocampal CA1 pyramidal cell layer in maleGluA1-KO mice, while not affecting c-Fos levels in WT mice. In female mice, no significant effect for LY354740 (15 mg/kg) on hyperactive behavior or hippocampal c-Fos was observed in either genotype or treatment cohort. A higher dose of LY354740 (30 mg/kg) alleviated hyperlocomotion of GluA1-KO males, but not that of GluA1-KO females. In conclusion, the excessive behavioral hyperactivity of GluA1-KO mice can be partly prevented by reducing neuronal excitability in the hippocampus with the mGluR2/3 agonist suggesting that the hippocampal reactivity is strongly involved in the behavioral phenotype of GluA1-KO mice.
authors.affiliation: Institute of Biomedicine/Pharmacology, Biomedicum Helsinki, P.O.B. 63, FIN-00014 University of Helsinki, Finland.
authors.forename: C
authors.initials: C
authors.lastname: Procaccini
authors.forename: M
authors.initials: M
authors.lastname: Maksimovic
authors.forename: T
authors.initials: T
authors.lastname: Aitta-Aho
authors.forename: E R
authors.initials: ER
authors.lastname: Korpi
authors.forename: A-M
authors.initials: AM
authors.lastname: Linden
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D004777:Environment; D005260:Female; D016762:Genes, fos / Q000235:genetics; D005838:Genotype; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006948:Hyperkinesis / Q000139:chemically induced* / Q000523:psychology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D018091:Receptors, AMPA / Q000235:genetics* / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012727:Sex Characteristics
chemical_list: D001643:Bridged Bicyclo Compounds; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C104753:eglumetad
keywords: (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide; AMPA; AMPA receptor; ANOVA; BSA; DG; EAAT1/GLAST; KO; LY354740; NBQX; TBS; TBS supplemented with 0.05% Tween 20; TBST; Tris-buffered saline; WT; analysis of variance; bovine serum albumin; dentate gyrus; excitatory amino acid transporter 1; hippocampus; hyperlocomotion; immediate early genes; knockout; mGlu2/3 receptor; mGluR; metabotropic glutamate receptors; novelty; wildtype; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid