title: Loss of GluN2D subunit results in social recognition deficit, social stress, 5-HT2Creceptor dysfunction, and anhedonia in mice.
abstract: The N-methyl-d-aspartate (NMDA) receptor channel is involved in various physiological functions, including learning and memory. The GluN2D subunit of the NMDA receptor has low expression in the mature brain, and its role is not fully understood. In the present study, the effects of GluN2D subunit deficiency on emotional and cognitive function were investigated in GluN2D knockout (KO) mice. We found a reduction of motility (i.e., a depressive-like state) in the tail suspension test and a reduction of sucrose preference (i.e., an anhedonic state) in GluN2D KO mice that were group-housed with littermates. Despite apparently normal olfactory function and social interaction, GluN2D KO mice exhibited a decrease in preference for social novelty, suggesting a deficit in social recognition or memory. Golgi-Cox staining revealed a reduction of the complexity of dendritic trees in the accessory olfactory bulb in GluN2D KO mice, suggesting a deficit in pheromone processing pathway activation, which modulates social recognition. The deficit in social recognition may result in social stress in GluN2D KO mice. Isolation housing is a procedure that has been shown to reduce stress in mice. Interestingly, 3-week isolation and treatment with agomelatine or the 5-hydroxytryptamine-2C (5-HT2C) receptor antagonist SB242084 reversed the anhedonic-like state in GluN2D KO mice. In contrast, treatment with the 5-HT2Creceptor agonist CP809101 induced depressive- and anhedonic-like states in isolated GluN2D KO mice. These results suggest that social stress that is caused by a deficit in social recognition desensitizes 5-HT2creceptors, followed by an anhedonic- and depressive-like state, in GluN2D KO mice. The GluN2D subunit of the NMDA receptor appears to be important for the recognition of individuals and development of normal emotionality in mice. 5-HT2Creceptor antagonism may be a therapeutic target for treating social stress-induced anhedonia. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Laboratory of Molecular Psychopharmacology, Graduate School of Nanosciences, Yokohama City University, Yokohama 236-0027, Japan. Electronic address: yamamoto-hd@igakuken.or.jp.
authors.forename: Hideko
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Kamegaya
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hagino
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Takamatsu
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Sawada
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Laboratory of Molecular Psychopharmacology, Graduate School of Nanosciences, Yokohama City University, Yokohama 236-0027, Japan.
authors.forename: Maaya
authors.initials: M
authors.lastname: Matsuzawa
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ide
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Laboratory of Molecular Psychopharmacology, Graduate School of Nanosciences, Yokohama City University, Yokohama 236-0027, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Ritsumeikan University Research Organization of Science and Technology, Kusatsu 525-8577, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D059445:Anhedonia / Q000502:physiology*; D000818:Animals; D003712:Dendrites / Q000473:pathology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009830:Olfactory Bulb / Q000473:pathology; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*; D021641:Recognition, Psychology / Q000502:physiology*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D012919:Social Behavior; D012934:Social Isolation; D013315:Stress, Psychological / Q000503:physiopathology*; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000631:Aminopyridines; D007211:Indoles; D021122:Protein Subunits; D044405:Receptor, Serotonin, 5-HT2C; D016194:Receptors, N-Methyl-D-Aspartate; D058830:Serotonin 5-HT2 Receptor Antagonists; C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; C464436:NR2D NMDA receptor; C084711:agomelatine; D009281:Naphthalenes
keywords: 5-Hydroxytryptamine-2C; Anhedonia; Behavior; Deficit in social recognition; Depression; GluN2D subunit; Golgi-Cox staining