title: Repeated stress-induced expression pattern alterations of the hippocampal chloride transporters KCC2 and NKCC1 associated with behavioral abnormalities in female mice.
abstract: The balance of cation-chloride co-transporters, particularly KCC2 and NKCC1, is critical for GABAergic inhibitory signaling. However, KCC2/NKCC1 balance is disrupted in many neurodegenerative diseases. Moreover, correlations between chronic stress, KCC2 and NKCC1 in the hippocampus remain poorly understood. Despite the fact that emotional disorders in humans are far more prevalent in women, there have been relatively few studies about female subjects. Here we investigated behaviors and expression patterns of KCC2 and NKCC1 in the hippocampi of female mice under chronic stress. Repeated stress (RS) was induced in experimental mice by repeated forced water administration. Then, expression patterns of GABAergic signaling molecules were identified by immunohistochemical analysis and performance was assessed using several behavioral tests. The results of semi-quantitative analysis showed that RS decreased KCC2 expression and increased NKCC1 expression in membranes of granular and pyramidal cells in the hippocampus. The novel object recognition (NOR) test and sociability test revealed that RS induced cognitive and sociability deficits, whereas RS increased the time spent in the open arms of the elevated plus maze test and induced attention deficits in other tests. In summary, RS induced alterations in membrane KCC2/NKCC1 balance in the hippocampus of female mice, which may contribute to GABAergic disinhibition associated with cognitional, sociability and attention deficits.
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima 890-8544, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Tsukahara
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima 890-8544, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Masuhara
authors.affiliation: Department of Oral Anatomy and Cell Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima 890-854, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Iwai
authors.affiliation: Department of Anatomy II, School of Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sonomura
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Kagoshima 890-8544, Japan. Electronic address: tomsato@dent.kagoshima-u.ac.jp.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Sato
mesh_terms: D000818:Animals; D001288:Attention; D002462:Cell Membrane / Q000378:metabolism; D003071:Cognition; D005106:Exploratory Behavior; D005260:Female; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D017966:Pyramidal Cells / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D012919:Social Behavior; D064506:Solute Carrier Family 12, Member 2 / Q000235:genetics* / Q000378:metabolism; D013315:Stress, Psychological / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D013550:Swimming; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D014867:Water / Q000008:administration & dosage; D000096922:K Cl- Cotransporters
chemical_list: D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D014867:Water; D000096922:K Cl- Cotransporters; C578878:Slc12a2 protein, mouse
keywords: GABA; KCC2; NKCC1; Stress