title: Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes.
abstract: Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of schizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a microRNA engineered to target specifically Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in γ-aminobutyric acid (GABA) release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in the prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic (Tg) mice uncovered that the Pvalb/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty-seeking and reduced fear extinction. Furthermore, NMDA (N-methyl-d-aspartate) receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABAergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia.
authors.affiliation: Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA.|Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA.|Neuroscience Graduate Program, Vanderbilt University, Nashville, TN, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Ramikie
authors.affiliation: Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA.|Neuroscience Graduate Program, Vanderbilt University, Nashville, TN, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Schmidt
authors.affiliation: Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Báldi
authors.affiliation: Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Garbett
authors.affiliation: Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Everheart
authors.affiliation: Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Warren
authors.affiliation: Department of Psychiatry, University of Szeged, Szeged, Hungary.
authors.forename: L
authors.initials: L
authors.lastname: Gellért
authors.affiliation: Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA.|Department of Psychiatry, University of Szeged, Szeged, Hungary.
authors.forename: S
authors.initials: S
authors.lastname: Horváth
authors.affiliation: Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA.|Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.affiliation: Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA.|Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN, USA.|Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA.|Department of Psychiatry, University of Szeged, Szeged, Hungary.
authors.forename: Károly
authors.initials: K
authors.lastname: Mirnics
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000502:physiology; D004195:Disease Models, Animal; D004594:Electrophysiology; D005106:Exploratory Behavior; D005239:Fear; D020868:Gene Silencing; D005968:Glutamate Decarboxylase / Q000235:genetics*; D007395:Interneurons / Q000378:metabolism*; D007649:Ketamine / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D010320:Parvalbumins / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012559:Schizophrenia / Q000235:genetics*; D055139:Sensory Gating / Q000235:genetics; D009435:Synaptic Transmission
chemical_list: D010320:Parvalbumins; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1