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Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes

Molecular Psychiatry volume 20, pages 1499–1507 (2015)Cite this article

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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.

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Acknowledgements

This work was supported by National Institutes of Health R01 MH067234 (to KM), R01 R21-MH103515 and K08 MH090412 (to SP) and by the NICHD P30 HD15052 grant awarded to the Vanderbilt Kennedy Center for Research on Human Development. JAB is supported by the 2T32MH065215-11 T32 NIH fellowship, whereas MJS was supported by the Vanderbilt Neuroscience Scholars Award. RB is supported by the generosity of Rosztoczy Foundation. We thank the Vanderbilt Murine Neurobehavioral Laboratory, especially Gregg Stanwood and John Allison, for consultation on behavioral tasks and equipment.

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Authors and Affiliations

  1. Department of Psychiatry, Psychiatry and Kennedy Center, Vanderbilt University, Nashville, TN, USA

    J A Brown, T S Ramikie, M J Schmidt, R Báldi, K Garbett, M G Everheart, S Horváth, S Patel & Károly Mirnics

  2. Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN, USA

    J A Brown & Károly Mirnics

  3. Neuroscience Graduate Program, Vanderbilt University, Nashville, TN, USA

    T S Ramikie & M J Schmidt

  4. Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA

    L E Warren & Károly Mirnics

  5. Department of Psychiatry, University of Szeged, Szeged, Hungary

    L Gellért, S Horváth & Károly Mirnics

  6. Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

    S Patel

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Brown, J., Ramikie, T., Schmidt, M. et al. Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. Mol Psychiatry 20, 1499–1507 (2015). https://doi.org/10.1038/mp.2014.192

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