Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes

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-positi...

Full description

Saved in:

Bibliographic Details
Published in:	Molecular psychiatry Vol. 20; no. 12; pp. 1499 - 1507
Main Authors:	Brown, J A, Ramikie, T S, Schmidt, M J, Báldi, R, Garbett, K, Everheart, M G, Warren, L E, Gellért, L, Horváth, S, Patel, S, Mirnics, Károly
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-12-2015 Nature Publishing Group
Subjects:	42/89 631/378 64/110 Acids Animals Artificial chromosomes Bacterial artificial chromosomes Behavior, Animal Behavioral Sciences Biological diversity conservation Biological Psychology Brain - physiology Care and treatment Channel gating Development and progression Disease Models, Animal Dosage Electrophysiology Enzymes Exploratory Behavior Fear Fear conditioning GAD1 gene Gene Silencing Glutamate decarboxylase Glutamate Decarboxylase - genetics Glutamatergic transmission Glutamic acid Glutamic acid receptors (ionotropic) Immunohistochemistry Interneurons Interneurons - metabolism Ketamine Ketamine - administration & dosage Laboratory animals Male Medicine Medicine & Public Health Mental disorders Methyl aspartate Mice Mice, Inbred C3H Mice, Transgenic MicroRNAs miRNA N-Methyl-D-aspartic acid receptors Neurosciences original-article Parvalbumins - metabolism Patient outcomes Pharmacotherapy Phenotypes Prefrontal cortex Psychiatry Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Risk factors Schizophrenia Schizophrenia - genetics Sensorimotor gating Sensory Gating - genetics Synaptic Transmission Transcription Transgenic mice γ-Aminobutyric acid United States United States > US Nashville Tennessee
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1359-4184 1476-5578
DOI:	10.1038/mp.2014.192