Abstract

The cAMP and cAMP-dependent protein kinase A (PKA) signaling cascade is a ubiquitous pathway acting downstream of multiple neuromodulators. We found that the phosphorylation of phosphodiesterase-4 (PDE4) by cyclin-dependent protein kinase 5 (Cdk5) facilitated cAMP degradation and homeostasis of cAMP/PKA signaling. In mice, loss of Cdk5 throughout the forebrain elevated cAMP levels and increased PKA activity in striatal neurons, and altered behavioral responses to acute or chronic stressors. Ventral striatum– or D1 dopamine receptor–specific conditional knockout of Cdk5, or ventral striatum infusion of a small interfering peptide that selectively targeted the regulation of PDE4 by Cdk5, produced analogous effects on stress-induced behavioral responses. Together, our results demonstrate that altering cAMP signaling in medium spiny neurons of the ventral striatum can effectively modulate stress-induced behavioral states. We propose that targeting the Cdk5 regulation of PDE4 could be a new therapeutic approach for clinical conditions associated with stress, such as depression.

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Acknowledgements

We thank N. Heintz (Rockefeller University) and GenSat for D1R-Cre mice, K. Deisseroth (Stanford University) for the Dio-Cre vector, C. Burger (University of Wisconsin-Madison) for AAV vectors, H. Ball and Y. Li (University of Texas Southwestern (UTSW) Protein Technology Center) for peptides, the UTSW Animal Resource Center for help with phosphorylation state–specific antibody generation, D.M. Dietz, M. Lutter, M. Kouser and J. Kumar for help with the social defeat procedure, and T. Singh and G. Mettlach for technical assistance. We thank M. Trivedi and the UTSW Depression Center for support. This work was supported by a Brain and Behavior Research Foundation NARSAD Young Investigator Award (K.H.), a pre-doctoral National Research Service Award from the National Institute on Drug Abuse (D.R.B.), a grant from the Darrell K Royal Research Fund for Alzheimer's Research (F.P.) and the California Metabolic Research Foundation (M.D.H.), as well as by US National Institutes of Health grants to A.C.N. and P.G. (MH090963, DA10044), E.J.N. (MH51399), R.T. (GM084249) and J.A.B. (MH79710, MH083711, DA016672, DA018343, DA033485, NS073855).

Author information

Author notes

    • Kanehiro Hayashi
    •  & David R Benavides

    Present addresses: Department of Anatomy, Keio University School of Medicine, Tokyo, Japan (K.H.), and Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA (D.R.B.).

Affiliations

  1. Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Florian Plattner
    • , Kanehiro Hayashi
    • , Adan Hernández
    • , David R Benavides
    • , Tara C Tassin
    • , Chunfeng Tan
    • , Matthew S Goldberg
    •  & James A Bibb
  2. Division of Neuroscience and Molecular Pharmacology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK.

    • Jonathan Day
  3. Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Maggy W Fina
    •  & Ronald Taussig
  4. Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York, USA.

    • Eunice Y Yuen
    •  & Zhen Yan
  5. Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Matthew S Goldberg
    •  & James A Bibb
  6. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Angus C Nairn
  7. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.

    • Angus C Nairn
    •  & Paul Greengard
  8. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Eric J Nestler
  9. Department of Pharmacology, Kurume University School of Medicine, Fukuoka, Japan.

    • Akinori Nishi
  10. Institute of Pharmaceutical Science, King's College London, London, UK.

    • Miles D Houslay
  11. Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • James A Bibb

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Contributions

F.P., K.H., D.R.B., A.H., T.C.T., C.T., J.D., M.W.F., E.Y.Y., M.S.G. and A.N. collected data and analyzed the experiments. F.P., Z.Y., A.C.N., E.J.N., A.N., P.G., R.T., M.D.H. and J.A.B. contributed to study design, supervision and interpretation of the experiments. F.P. and J.A.B. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to James A Bibb.

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https://doi.org/10.1038/nn.4066

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