title: Reversal of novelty-induced hippocampal c-Fos expression in GluA1 subunit-deficient mice by chronic treatment targeting glutamatergic transmission.
abstract: Malfunction of glutamate transmission is implicated in several neuropsychiatric disorders. Gria1-/- mouse line with knocked-out GluA1 subunits of ionotropic AMPA glutamate receptor displays several behavioural features of schizoaffective disorder. Typically, these mice show hyperactivity provoked by environmental novelty, which is attenuated after 4-week treatment with the standard mood-stabilisers lithium and valproate and the mood-stabilising anticonvulsants topiramate and lamotrigine (Maksimovic, M., Vekovischeva, O.Y., Aitta-Aho, T., Korpi, E.R., 2014. Chronic treatment with mood-stabilizers attenuates abnormal hyperlocomotion of GluA1-subunit deficient mice. PloS One. 9, e100188). Here, we complement our study by treating these mice chronically with perampanel, a novel non-competitive antagonist of AMPA receptors, for 4 weeks at the dose of 60 mg/kg diet, and found reduced locomotor hyperactivity in the Gria1-/- animals, while not affecting the wild-type littermates. To study the cellular mechanism by which chronic treatments with glutamate-modulating mood-stabilizing drugs alleviate this hyperactivity, we used the immediate early gene c-Fos protein expression as a marker of neuronal activity in the brain. Chronic lithium, valproate and topiramate blunted the c-Fos expression especially in the dorsal hippocampus of the Gria1-/- mice, with all of them reducing the number of c-Fos-positive cells in the CA3 region and valproate and topiramate also in the dentate gyrus (DG). Lamotrigine and perampanel treatments had the same effect in the all CA1, CA3 and DG subfields of the dorsal hippocampus of Gria1-/- mice. The results suggest that abnormal (hippocampal) glutamatergic transmission underlies the hyperactive phenotype of the Gria1-/- mice in a novel environment, and based on the efficacies of the present chronic drug treatments, this mouse model may serve as a predictive tool for studying novel mood-stabilisers.
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.
authors.forename: Milica
authors.initials: M
authors.lastname: Maksimovic
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Aitta-aho
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Finland; Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, Singapore; SINAPSE, Singapore Institute for Neurotechnology, Singapore. Electronic address: esa.korpi@helsinki.fi.
authors.forename: Esa R
authors.initials: ER
authors.lastname: Korpi
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D000077213:Lamotrigine; D018020:Lithium Compounds / Q000008:administration & dosage; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011728:Pyridones / Q000008:administration & dosage; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission; D000077236:Topiramate; D014227:Triazines / Q000008:administration & dosage; D014635:Valproic Acid / Q000008:administration & dosage
chemical_list: D005632:Fructose; D018698:Glutamic Acid; D000077213:Lamotrigine; D018020:Lithium Compounds; D018696:Neuroprotective Agents; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; D011728:Pyridones; D018091:Receptors, AMPA; D000077236:Topiramate; D014227:Triazines; D014635:Valproic Acid; C551441:perampanel
keywords: Anti-mania drugs; GluA1 subunit knockout; Hyperactivity; Lamotrigine (PubChem CID: 3878); Lithium carbonate (PubChem CID: 11125); Mouse model; Perampanel; Perampanel (PubChem CID: 9924495); Schizoaffective disorder; Sodium valproate (PubChem CID: 16760703); Topiramate (PubChem CID: 5284627)