title: Schizophrenia-like phenotypes in mice with NMDA receptor ablation in intralaminar thalamic nucleus cells and gene therapy-based reversal in adults.
abstract: In understanding the mechanism of schizophrenia pathogenesis, a significant finding is that drug abuse of phencyclidine or its analog ketamine causes symptoms similar to schizophrenia. Such drug effects are triggered even by administration at post-adolescent stages. Both drugs are N-methyl-d-aspartate receptor (NMDAR) antagonists, leading to a major hypothesis that glutamate hypofunction underlies schizophrenia pathogenesis. The precise region that depends on NMDAR function, however, is unclear. Here, we developed a mouse strain in which NMDARs in the intralaminar thalamic nuclei (ILN) were selectively disrupted. The mutant mice exhibited various schizophrenia-like phenotypes, including deficits in working memory, long-term spatial memory, and attention, as well as impulsivity, impaired prepulse inhibition, hyperlocomotion and hyperarousal. The electroencephalography analysis revealed that the mutant mice had a significantly reduced power in a wide range of frequencies including the alpha, beta and gamma bands, both during wake and rapid eye movement (REM) sleep, and a modest decrease of gamma power during non-REM sleep. Notably, restoring NMDARs in the adult ILN rescued some of the behavioral abnormalities. These findings suggest that NMDAR dysfunction in the ILN contributes to the pathophysiology of schizophrenia-related disorders. Furthermore, the reversal of inherent schizophrenia-like phenotypes in the adult mutant mice supports that ILN is a potential target site for a therapeutic strategy.
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Saitama, Japan.|Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Science, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: T
authors.identifier: 0000-0002-5508-418X
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kashiwagi
authors.affiliation: Laboratory for Local Neuronal Circuits, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Nakagawa
authors.affiliation: Biotechnological Optics Research Team, RIKEN Center for Advanced Photonics, Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Michikawa
authors.affiliation: Laboratory for Neuron-Glia Circuitry, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Ando
authors.affiliation: Laboratory for Circuit and Behavioral Physiology, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Huang
authors.affiliation: Laboratory for Local Neuronal Circuits, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hosoya
authors.affiliation: Laboratory for Circuit and Behavioral Physiology, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: T J
authors.initials: TJ
authors.lastname: McHugh
authors.affiliation: Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Science, The University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kuwahara
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Itohara
mesh_terms: D000818:Animals; D001143:Arousal; D001288:Attention; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004569:Electroencephalography; D015316:Genetic Therapy; D007175:Impulsive Behavior; D020646:Intralaminar Thalamic Nuclei / Q000378:metabolism*; D008124:Locomotion; D008297:Male; D018782:Maze Learning; D008570:Memory, Short-Term; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D065808:Prepulse Inhibition; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D012565:Schizophrenic Psychology; D065852:Spatial Memory
chemical_list: C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate