Abstract

Millions of people regularly obtain insufficient sleep1. Given the effect of sleep deprivation on our lives, understanding the cellular and molecular pathways affected by sleep deprivation is clearly of social and clinical importance. One of the major effects of sleep deprivation on the brain is to produce memory deficits in learning models that are dependent on the hippocampus2,3,4,5. Here we have identified a molecular mechanism by which brief sleep deprivation alters hippocampal function. Sleep deprivation selectively impaired 3′, 5′-cyclic AMP (cAMP)- and protein kinase A (PKA)-dependent forms of synaptic plasticity6 in the mouse hippocampus, reduced cAMP signalling, and increased activity and protein levels of phosphodiesterase 4 (PDE4), an enzyme that degrades cAMP. Treatment of mice with phosphodiesterase inhibitors rescued the sleep-deprivation-induced deficits in cAMP signalling, synaptic plasticity and hippocampus-dependent memory. These findings demonstrate that brief sleep deprivation disrupts hippocampal function by interfering with cAMP signalling through increased PDE4 activity. Thus, drugs that enhance cAMP signalling may provide a new therapeutic approach to counteract the cognitive effects of sleep deprivation.

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Acknowledgements

We thank A. Sehgal and J. Hawk for their comments on the manuscript. We thank J. O’Donnell for his help with planning rolipram treatment experiments. We thank J. Bibb for discussions and comments on the manuscript. We thank S. Fluharty and J. Lindstrom for the use of their gamma scintillation counters, and T. Bale, N. Goel, K. Semsar and S. Teegarden for their help with corticosterone assays. We also thank P. Hernandez, N. Khatib, A. Park, J. Lederman, C. Florian and W. Lu for their help with experiments. This research was supported by Systems and Integrative Biology Training grant GM07517 (to C.G.V., M. Nusbaum PI), NIH training grant HL07953 (to C.G.V., A. I. Pack PI), the Netherlands Organization for Scientific Research NWO-Rubicon grant 825.07.029 (to R.H.), the National Institutes of Health (AG017628; to T.A., A. I. Pack PI), SCOR grant HL060287 (to T.A., A. I. Pack PI), HFSP grant RGSP/2005 (to T.A.), the Medical Research Council (UK) grant G0600765 (to M.D.H. and G.S.B.), the European Union grant LSHB-CT-2006-037189 (to M.D.H.), the Fondation Leducq grant 06CVD02 (to M.D.H. and G.S.B.), CIHR84256 (to M.Z.), and a UK Engineering and Physical Sciences Research Council training grant (to K.M.B.).

Author Contributions Experiments were conceived and designed by C.G.V., T.A., G.S.B., M.D.H. and M.Z. Behavioural and gene expression experiments were carried out by D.J. and C.G.V. Electrophysiological recordings were carried out by C.G.V. and T.H. cAMP assays were carried out by C.G.V. Western blots were carried out by K.M.B. PDE activity assays were carried out by G.S.B. Immunohistochemistry experiments were carried out by R.H. and A.D. EEG/EMG recordings were carried out by M.W. Sleep deprivation and electrophysiology for whole-cell patch-clamp recordings were performed by X.-Y.L., G.D., S.S.K., T.C. and Y.-Z.S. Manuscript was prepared by C.G.V. and T.A., with input from D.J., R.H., M.W., G.S.B. and M.D.H.

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  1. Neuroscience Graduate Group,

    • Christopher G. Vecsey
    • , Mathieu Wimmer
    •  & Ted Huang
  2. Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Christopher G. Vecsey
    • , Devan Jaganath
    • , Robbert Havekes
    • , Andrew Daniels
    • , Mathieu Wimmer
    • , Ted Huang
    •  & Ted Abel
  3. Neuroscience and Molecular Pharmacology, Wolfson and Davidson Buildings, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK

    • George S. Baillie
    • , Kim M. Brown
    •  & Miles D. Houslay
  4. Department of Physiology, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada

    • Xiang-Yao Li
    • , Giannina Descalzi
    • , Susan S. Kim
    • , Tao Chen
    • , Yu-Ze Shang
    •  & Min Zhuo

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