title: Cortical Gene Expression After a Conditional Knockout of 67 kDa Glutamic Acid Decarboxylase in Parvalbumin Neurons.
abstract: In the cortex of subjects with schizophrenia, expression of glutamic acid decarboxylase 67 (GAD67), the enzyme primarily responsible for cortical GABA synthesis, is reduced in the subset of GABA neurons that express parvalbumin (PV). This GAD67 deficit is accompanied by lower cortical levels of other GABA-associated transcripts, including GABA transporter-1, PV, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B, somatostatin, GABAA receptor α1 subunit, and KCNS3 potassium channel subunit mRNAs. In contrast, messenger RNA (mRNA) levels for glutamic acid decarboxylase 65 (GAD65), another enzyme for GABA synthesis, are not altered. We tested the hypothesis that this pattern of GABA-associated transcript levels is secondary to the GAD67 deficit in PV neurons by analyzing cortical levels of these GABA-associated mRNAs in mice with a PV neuron-specific GAD67 knockout. Using in situ hybridization, we found that none of the examined GABA-associated transcripts had lower cortical expression in the knockout mice. In contrast, PV, BDNF, KCNS3, and GAD65 mRNA levels were higher in the homozygous mice. In addition, our behavioral test battery failed to detect a change in sensorimotor gating or working memory, although the homozygous mice exhibited increased spontaneous activities. These findings suggest that reduced GAD67 expression in PV neurons is not an upstream cause of the lower levels of GABA-associated transcripts, or of the characteristic behaviors, in schizophrenia. In PV neuron-specific GAD67 knockout mice, increased levels of PV, BDNF, and KCNS3 mRNAs might be the consequence of increased neuronal activity secondary to lower GABA synthesis, whereas increased GAD65 mRNA might represent a compensatory response to increase GABA synthesis.
authors.affiliation: Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan;
authors.forename: Danko
authors.initials: D
authors.lastname: Georgiev
authors.affiliation: Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan;
authors.forename: Toru
authors.initials: T
authors.lastname: Yoshihara
authors.affiliation: Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan;
authors.forename: Rika
authors.initials: R
authors.lastname: Kawabata
authors.affiliation: Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan;
authors.forename: Takurou
authors.initials: T
authors.lastname: Matsubara
authors.affiliation: Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan;
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsubomoto
authors.affiliation: Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan;
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Minabe
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA; Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA.
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.affiliation: Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA; takanori@med.kanazawa-u.ac.jp.
authors.forename: Takanori
authors.initials: T
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008570:Memory, Short-Term; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010320:Parvalbumins / Q000378:metabolism*; D065808:Prepulse Inhibition; D012559:Schizophrenia / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D010320:Parvalbumins; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: cerebral cortex; in situ hybridization; mouse; prepulse inhibition; schizophrenia; working memory