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Serum Response Factor (SRF) Ablation Interferes with Acute Stress-Associated Immediate and Long-Term Coping Mechanisms

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Abstract

Stress experience modulates behavior, metabolism, and energy expenditure of organisms. One molecular hallmark of an acute stress response is a rapid induction of immediate early genes (IEGs) such as c-Fos and Egr family members. IEG transcription in neurons is mediated by the neuronal activity-driven gene regulator serum response factor (SRF). We show a first role of SRF in immediate and long-lasting acute restraint stress (AS) responses. For this, we employed a standardized mouse phenotyping protocol at the German Mouse Clinic (GMC) including behavioral, metabolic, and cardiologic tests as well as gene expression profiling to analyze the consequences of forebrain-specific SRF deletion in mice exposed to AS. Adult mice with an SRF deletion in glutamatergic neurons (Srf; CaMKIIa-CreERT2) showed hyperactivity, decreased anxiety, and impaired working memory. In response to restraint AS, instant stress reactivity including locomotor behavior and corticosterone induction was impaired in Srf mutant mice. Interestingly, even several weeks after previous AS exposure, SRF-deficient mice showed long-lasting AS-associated changes including altered locomotion, metabolism, energy expenditure, and cardiovascular changes. This suggests a requirement of SRF for mediating long-term stress coping mechanisms in wild-type mice. SRF ablation decreased AS-mediated IEG induction and activity of the actin severing protein cofilin. In summary, our data suggest an SRF function in immediate AS reactions and long-term post-stress-associated coping mechanisms.

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Acknowledgements

We would like to thank the GMC technicians, the GMC animal caretaker team, and Daniela Sinske for expert technical assistance.

B.K. is supported by the Deutsche Forschungsgemeinschaft (DFG) through SFB1149, an Ulm University and Bundeswehrkrankenhaus research initiative, and the Schram, Gottschalk and Gemeinnützige Hertie foundation.

This work has also been funded by the German Federal Ministry of Education and Research to the GMC (Infrafrontier grant 01KX1012), by the Helmholtz Alliance ICEMED—Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Network Fund of the Helmholtz Association, by the Helmholtz Portfolio Theme “Metabolic Dysfunction and Common Disease,” and by the DFG grant “DJ-1 Linked Neurodegeneration Pathways in New Mouse Models of Parkinson’s Disease” (WU 164/5-1).

Author Contributions

A.Z., G.M., C.M.R., S.A., P.F., L.G., S.M.H., L.B, J.R., C.P., B.R., and K.M. conducted experiments. W.W., T.K., M.K., J.A., E.W., R.B., H.F., V.G.D., and M.H.A. supervised experiments. B.K. supervised and designed experiments and wrote the paper.

The manuscript is accompanied by Additional material:

Supplemental Figs. (S1–S8) Supplement with detailed materials and methods and supplemental references

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Authors and Affiliations

  1. German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany

    Annemarie Zimprich, Lillian Garrett, Sabine M. Hölter, Lore Becker, Jan Rozman, Cornelia Prehn, Birgit Rathkolb, Kristin Moreth, Jerzy Adamski, Helmut Fuchs, Valerie Gailus-Durner & Martin Hrabe de Angelis

  2. Institute of Developmental Genetics, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany

    Annemarie Zimprich, Lillian Garrett, Sabine M. Hölter & Wolfgang Wurst

  3. Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany

    Gabi Mroz, Christopher Meyer zu Reckendorf, Sofia Anastasiadou, Philip Förstner & Bernd Knöll

  4. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, 81377, Munich, Germany

    Birgit Rathkolb & Eckhard Wolf

  5. Chair of Developmental Genetics, Technische Universität München-Weihenstephan, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany

    Wolfgang Wurst

  6. German Center for Neurodegenerative Diseases (DZNE), Munich Site, Feodor-Lynen-Strasse 17, 81377, Munich, Germany

    Wolfgang Wurst & Thomas Klopstock

  7. Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Schillerstr. 44, 80336, Munich, Germany

    Wolfgang Wurst & Thomas Klopstock

  8. Department of Neurology, Friedrich-Baur-Institute, Klinikum der Ludwig-Maximilians-Universität München, Ziemssenstr. 1a, 80336, Munich, Germany

    Thomas Klopstock

  9. Molecular Nutritional Medicine Else Kröner-Fresenius Center, Technische Universität München, 85354, Freising-Weihenstephan, Germany

    Martin Klingenspor

  10. ZIEL—Center for Nutrition and Food Sciences, Technische Universität München, 85350, Freising, Germany

    Martin Klingenspor

  11. Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Raffi Bekeredjian

  12. Chair of Experimental Genetics, School of Life Science Weihenstephan Technische Universität München, Alte Akademie 8, 85354, Freising, Germany

    Jerzy Adamski & Martin Hrabe de Angelis

  13. German Center for Diabetes Research (DZD), Ingostädter Landstr. 1, 85764, Neuherberg, Germany

    Jan Rozman, Birgit Rathkolb, Jerzy Adamski & Martin Hrabe de Angelis

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  1. Annemarie Zimprich
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Corresponding author

Correspondence to Bernd Knöll.

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The authors declare that they have no competing interests.

Additional information

Annemarie Zimprich and Gabi Mroz contributed equally to this work.

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Zimprich, A., Mroz, G., Meyer zu Reckendorf, C. et al. Serum Response Factor (SRF) Ablation Interferes with Acute Stress-Associated Immediate and Long-Term Coping Mechanisms. Mol Neurobiol 54, 8242–8262 (2017). https://doi.org/10.1007/s12035-016-0300-x

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