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Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Molecular Psychiatry volume 14, pages 332–346 (2009)Cite this article

Abstract

Activin, a member of the transforming growth factor-β superfamily, affords neuroprotection in acute brain injury, but its physiological functions in normal adult brain are largely unknown. Using transgenic (tg) mice expressing a dominant-negative activin receptor mutant under the control of the CaMKIIα promoter in forebrain neurons, we identified activin as a key regulator of γ-aminobutyric acid (GABA)ergic synapses and anxiety-like behavior. In the open field, wild-type (wt) and tg mice did not differ in spontaneous locomotion and exploration behavior. However, tg mice visited inner fields significantly more often than wt mice. In the light–dark exploration test, tg mice made more exits, spent significantly more time on a well-lit elevated bar and went farther away from the dark box as compared to wt mice. In addition, the anxiolytic effect of diazepam was abrogated in tg mice. Thus the disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABAB receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre- and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders: and drugs affecting this pathway might show promise for psychopharmacological treatment.

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Acknowledgements

We thank Didier Gremelle for technical assistance. We are grateful to Prof Dr Werner Sieghart (Vienna, Austria) for providing antibodies against the α4- and δ-subunit. This work was supported by the ETH Zurich, the Swiss National Science Foundation (grant no. 3100A0-109340/1 to SW) and the University of Kiel (to CA).

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Authors and Affiliations

  1. Institute of Physiology, University of Kiel, Kiel, Germany

    F Zheng & C Alzheimer

  2. Institute of Neuroscience, Technical University, Munich, Germany

    H Adelsberger

  3. Department of Biology, Institute of Cell Biology, ETH Zurich, Zurich, Switzerland

    M R Müller & S Werner

  4. Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

    J-M Fritschy

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  1. F Zheng
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Correspondence to C Alzheimer.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Zheng, F., Adelsberger, H., Müller, M. et al. Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior. Mol Psychiatry 14, 332–346 (2009). https://doi.org/10.1038/sj.mp.4002131

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