Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes

J. A. Brown, T. S. Ramikie, M. J. Schmidt, R. Báldi, K. Garbett, M. G. Everheart, L. E. Warren, L. Gellért, S. Horváth, S. Patel, Karoly Mirnics

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1499-1507
Number of pages9
JournalMolecular Psychiatry
Volume20
Issue number12
DOIs
StatePublished - Dec 1 2015

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Parvalbumins
Ketamine
Interneurons
Transgenic Mice
Fear
Schizophrenia
Sensory Gating
Aminobutyrates
Bacterial Artificial Chromosomes
Glutamate Decarboxylase
Pyramidal Cells
Prefrontal Cortex
MicroRNAs
gamma-Aminobutyric Acid
Protein Isoforms
Down-Regulation
Immunohistochemistry
Phenotype
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Brown, J. A., Ramikie, T. S., Schmidt, M. J., Báldi, R., Garbett, K., Everheart, M. G., ... Mirnics, K. (2015). Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. Molecular Psychiatry, 20(12), 1499-1507. https://doi.org/10.1038/mp.2014.192

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

In: Molecular Psychiatry, Vol. 20, No. 12, 01.12.2015, p. 1499-1507.

Research output: Contribution to journalArticle

Brown, JA, Ramikie, TS, Schmidt, MJ, Báldi, R, Garbett, K, Everheart, MG, Warren, LE, Gellért, L, Horváth, S, Patel, S & Mirnics, K 2015, 'Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes', Molecular Psychiatry, vol. 20, no. 12, pp. 1499-1507. https://doi.org/10.1038/mp.2014.192
Brown JA, Ramikie TS, Schmidt MJ, Báldi R, Garbett K, Everheart MG et al. Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. Molecular Psychiatry. 2015 Dec 1;20(12):1499-1507. https://doi.org/10.1038/mp.2014.192
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, Karoly. / Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. In: Molecular Psychiatry. 2015 ; Vol. 20, No. 12. pp. 1499-1507.
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