Regulating anxiety with extrasynaptic inhibition

  • Nature Neuroscience volume 18, pages 14931500 (2015)
  • doi:10.1038/nn.4102
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Aversive experiences can lead to complex behavioral adaptations including increased levels of anxiety and fear generalization. The neuronal mechanisms underlying such maladaptive behavioral changes, however, are poorly understood. Here, using a combination of behavioral, physiological and optogenetic approaches in mouse, we identify a specific subpopulation of central amygdala neurons expressing protein kinase C δ (PKCδ) as key elements of the neuronal circuitry controlling anxiety. Moreover, we show that aversive experiences induce anxiety and fear generalization by regulating the activity of PKCδ+ neurons via extrasynaptic inhibition mediated by α5 subunit-containing GABAA receptors. Our findings reveal that the neuronal circuits that mediate fear and anxiety overlap at the level of defined subpopulations of central amygdala neurons and demonstrate that persistent changes in the excitability of a single cell type can orchestrate complex behavioral changes.

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Change history

  • Corrected online 05 October 2015

    In the version of this article initially published, the grant number for U.R. was given as R01MH80006 instead of R01MH080006 and grants to J.M.C. from the National Institute of Neurological Disorders and Stroke (R01NS076517) and the National Institute of Mental Health (R01MH096463), US National Institutes of Health, were missing. The error has been corrected in the HTML and PDF versions of the article.


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We thank all members of the Lüthi laboratory for discussions and critical comments on the manuscript. In particularly, we thank P. Tovote, S. Wolff, S. Ciocchi, F. Grenier, J. Gruendemann, C. Müller, K. Bylund and A. Loche for comments and for technical support, and W. Sieghart (Medical University of Vienna) and D. Anderson (California Institute of Technology) for antibodies and mice. This work was supported by the Novartis Research Foundation, by the National Center of Competences in Research program 'SYNAPSY — The Synaptic Bases of Mental Diseases' (financed by the Swiss National Science Foundation (SNSF)) as well as by an SNSF core grant to A.L. J.P.F. was supported by a NARSAD fellowship. C.X. was supported by an EMBO Long-Term Fellowship. P.S. and L.X. were supported by the Australian National Health and Medical Research Council. U.R. was supported by grant R01MH080006 from the US National Institute of Mental Health, National Institutes of Health. Funding for J.M.C. was provided by the National Institute of Neurological Disorders and Stroke (R01NS076517) and the National Institute of Mental Health (R01MH096463), US National Institutes of Health. Y.K. and F.F. were supported by Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung) Sonderforschungsbereich grant F44-17.

Author information


  1. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

    • Paolo Botta
    • , Lynda Demmou
    • , Milica Markovic
    • , Chun Xu
    • , Jonathan P Fadok
    • , Tingjia Lu
    •  & Andreas Lüthi
  2. University of Basel, Basel, Switzerland.

    • Paolo Botta
    • , Lynda Demmou
    •  & Milica Markovic
  3. Department of Pharmacology, Innsbruck Medical University, Innsbruck, Austria.

    • Yu Kasugai
    •  & Francesco Ferraguti
  4. Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.

    • Michael M Poe
    •  & James M Cook
  5. Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia.

    • Li Xu
    •  & Pankaj Sah
  6. Laboratory of Genetic Neuropharmacology, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts, USA.

    • Uwe Rudolph


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The manuscript was prepared by A.L. and P.B. Electrophysiological recordings in vitro, behavioral experiments and viral injections were performed by P.B. Pharmacology combined with single-unit recordings in freely moving animals were designed and performed by L.D. In vivo recordings from optogenetically identified neurons were performed by M.M. and J.P.F. Immunohistochemistry was accomplished by C.X. T.L. cloned the conditional shRNA plasmid. M.M.P. and J.M.C. provided the PWZ-029. L.X. tested the shRNA efficacy on α5GABAAR protein in HEK293T cells and P.S. provided the plasmid expressing shRNA. U.R. provided perfused brains of α5−/− mice and of α5fl/fl mice. All electron microscopy experiments were performed and analyzed by Y.K. and F.F.

Competing interests

In the last 3 years, U.R. has received compensation for professional services from Concert Pharmaceuticals.

Corresponding author

Correspondence to Andreas Lüthi.

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