title: Glutamate Decarboxylase 67 Deficiency in a Subset of GABAergic Neurons Induces Schizophrenia-Related Phenotypes.
abstract: Decreased expression of the GABA synthetic enzyme glutamate decarboxylase 67 (GAD67) in a subset of GABAergic neurons, including parvalbumin (PV)-expressing neurons, has been observed in postmortem brain studies of schizophrenics and in animal models of schizophrenia. However, it is unclear whether and how the perturbations of GAD67-mediated GABA synthesis and signaling contribute to the pathogenesis of schizophrenia. To address this issue, we generated the mice lacking GAD67 primarily in PV neurons and characterized them with focus on schizophrenia-related parameters. We found that heterozygous mutant mice exhibited schizophrenia-related behavioral abnormalities such as deficits in prepulse inhibition, MK-801 sensitivity, and social memory. Furthermore, we observed reduced inhibitory synaptic transmission, altered properties of NMDA receptor-mediated synaptic responses in pyramidal neurons, and increased spine density in hippocampal CA1 apical dendrites, suggesting a possible link between GAD67 deficiency and disturbed glutamatergic excitatory synaptic functions in schizophrenia. Thus, our results indicate that the mice heterozygous for GAD67 deficiency primarily in PV neurons share several neurochemical and behavioral abnormalities with schizophrenia, offering a novel tool for addressing the underlying pathophysiology of schizophrenia.
authors.affiliation: 1] Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan [3] Department of Psychiatry and Human Behavior, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Fujihara
authors.affiliation: 1] Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Miwa
authors.affiliation: 1] Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kakizaki
authors.affiliation: 1] Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan [3] Institute of Experimental Animal Research, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kaneko
authors.affiliation: Department of Psychiatry and Human Behavior, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mikuni
authors.affiliation: Department of Morphological Neural Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Chiyoko
authors.initials: C
authors.lastname: Tanahira
authors.affiliation: Department of Morphological Neural Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Tamamaki
authors.affiliation: 1] Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D003712:Dendrites / Q000378:metabolism; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology*; D005968:Glutamate Decarboxylase / Q000172:deficiency* / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000473:pathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D010320:Parvalbumins / Q000235:genetics; D010641:Phenotype; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology*; D013004:Somatostatin / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000199:Actins; D018691:Excitatory Amino Acid Antagonists; D010320:Parvalbumins; D013004:Somatostatin; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D014633:Valine