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Mol Psychiatry. 2015 Dec;20(12):1499-507. doi: 10.1038/mp.2014.192. Epub 2015 Jan 27.

Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes.

Author information

1
Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA.
2
Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN, USA.
3
Neuroscience Graduate Program, Vanderbilt University, Nashville, TN, USA.
4
Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA.
5
Department of Psychiatry, University of Szeged, Szeged, Hungary.
6
Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.

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.

PMID:
25623945
PMCID:
PMC4516717
DOI:
10.1038/mp.2014.192
[Indexed for MEDLINE]
Free PMC Article

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