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Sleep deprivation impairs cAMP signalling in the hippocampus

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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Figure 1: Brief sleep deprivation specifically impairs forms of LTP that depend on the cAMP/PKA pathway.
Figure 2: PDE inhibition rescues impairments in FSK-induced cAMP levels and LTP produced by brief sleep deprivation.
Figure 3: Sleep deprivation increases PDE4 activity and protein levels in the hippocampus.
Figure 4: The PDE4 inhibitor rolipram rescues LTP and memory deficits caused by sleep deprivation.

References

  1. 1

    Hublin, C., Kaprio, J., Partinen, M. & Koskenvuo, M. Insufficient sleep—a population-based study in adults. Sleep 24, 392–400 (2001)

    CAS  Article  Google Scholar 

  2. 2

    Graves, L. A., Heller, E. A., Pack, A. I. & Abel, T. Sleep deprivation selectively impairs memory consolidation for contextual fear conditioning. Learn. Mem. 10, 168–176 (2003)

    Article  Google Scholar 

  3. 3

    Guan, Z., Peng, X. & Fang, J. Sleep deprivation impairs spatial memory and decreases extracellular signal-regulated kinase phosphorylation in the hippocampus. Brain Res. 1018, 38–47 (2004)

    CAS  Article  Google Scholar 

  4. 4

    McDermott, C. M. et al. Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons. J. Neurosci. 23, 9687–9695 (2003)

    CAS  Article  Google Scholar 

  5. 5

    Smith, C. & Rose, G. M. Evidence for a paradoxical sleep window for place learning in the Morris water maze. Physiol. Behav. 59, 93–97 (1996)

    CAS  Article  Google Scholar 

  6. 6

    Nguyen, P. V. & Woo, N. H. Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein kinases. Prog. Neurobiol. 71, 401–437 (2003)

    CAS  Article  Google Scholar 

  7. 7

    Martin, S. J., Grimwood, P. D. & Morris, R. G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000)

    CAS  Article  Google Scholar 

  8. 8

    Huang, Y. Y. & Kandel, E. R. Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization. Learn. Mem. 1, 74–82 (1994)

    CAS  PubMed  Google Scholar 

  9. 9

    Nguyen, P. V., Abel, T. & Kandel, E. R. Requirement of a critical period of transcription for induction of a late phase of LTP. Science 265, 1104–1107 (1994)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Nguyen, P. V. & Kandel, E. R. Brief theta-burst stimulation induces a transcription-dependent late phase of LTP requiring cAMP in area CA1 of the mouse hippocampus. Learn. Mem. 4, 230–243 (1997)

    CAS  Article  Google Scholar 

  11. 11

    Huber, R., Deboer, T. & Tobler, I. Effects of sleep deprivation on sleep and sleep EEG in three mouse strains: empirical data and simulations. Brain Res. 857, 8–19 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Scharf, M. T. et al. Protein synthesis is required for the enhancement of long-term potentiation and long-term memory by spaced training. J. Neurophysiol. 87, 2770–2777 (2002)

    CAS  Article  Google Scholar 

  13. 13

    Woo, N. H., Duffy, S. N., Abel, T. & Nguyen, P. V. Temporal spacing of synaptic stimulation critically modulates the dependence of LTP on cyclic AMP-dependent protein kinase. Hippocampus 13, 293–300 (2003)

    CAS  Article  Google Scholar 

  14. 14

    Morris, R. G., Anderson, E., Lynch, G. S. & Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-d-aspartate receptor antagonist, AP5. Nature 319, 774–776 (1986)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Lynch, G., Kessler, M., Halpain, S. & Baudry, M. Biochemical effects of high-frequency synaptic activity studied with in vitro slices. Fed. Proc. 42, 2886–2890 (1983)

    CAS  PubMed  Google Scholar 

  16. 16

    Campbell, I. G., Guinan, M. J. & Horowitz, J. M. Sleep deprivation impairs long-term potentiation in rat hippocampal slices. J. Neurophysiol. 88, 1073–1076 (2002)

    CAS  Article  Google Scholar 

  17. 17

    Chen, C., Hardy, M., Zhang, J., LaHoste, G. J. & Bazan, N. G. Altered NMDA receptor trafficking contributes to sleep deprivation-induced hippocampal synaptic and cognitive impairments. Biochem. Biophys. Res. Commun. 340, 435–440 (2006)

    CAS  Article  Google Scholar 

  18. 18

    Kopp, C., Longordo, F., Nicholson, J. R. & Luthi, A. Insufficient sleep reversibly alters bidirectional synaptic plasticity and NMDA receptor function. J. Neurosci. 26, 12456–12465 (2006)

    CAS  Article  Google Scholar 

  19. 19

    McDermott, C. M., Hardy, M. N., Bazan, N. G. & Magee, J. C. Sleep deprivation-induced alterations in excitatory synaptic transmission in the CA1 region of the rat hippocampus. J. Physiol. (Lond.) 570, 553–565 (2006)

    CAS  Article  Google Scholar 

  20. 20

    Tartar, J. L. et al. Hippocampal synaptic plasticity and spatial learning are impaired in a rat model of sleep fragmentation. Eur. J. Neurosci. 23, 2739–2748 (2006)

    Article  Google Scholar 

  21. 21

    Josselyn, S. A. & Nguyen, P. V. CREB, synapses and memory disorders: past progress and future challenges. Curr. Drug Targets CNS Neurol. Disord. 4, 481–497 (2005)

    CAS  Article  Google Scholar 

  22. 22

    Houslay, M. D. & Adams, D. R. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem. J. 370, 1–18 (2003)

    CAS  Article  Google Scholar 

  23. 23

    Wallace, D. A. et al. Identification and characterization of PDE4A11, a novel, widely expressed long isoform encoded by the human PDE4A cAMP phosphodiesterase gene. Mol. Pharmacol. 67, 1920–1934 (2005)

    CAS  Article  Google Scholar 

  24. 24

    McPhee, I., Cochran, S. & Houslay, M. D. The novel long PDE4A10 cyclic AMP phosphodiesterase shows a pattern of expression within brain that is distinct from the long PDE4A5 and short PDE4A1 isoforms. Cell. Signal. 13, 911–918 (2001)

    CAS  Article  Google Scholar 

  25. 25

    Houslay, M. D., Schafer, P. & Zhang, K. Y. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov. Today 10, 1503–1519 (2005)

    CAS  Article  Google Scholar 

  26. 26

    Frankland, P. W., Cestari, V., Filipkowski, R. K., McDonald, R. J. & Silva, A. J. The dorsal hippocampus is essential for context discrimination but not for contextual conditioning. Behav. Neurosci. 112, 863–874 (1998)

    CAS  Article  Google Scholar 

  27. 27

    Eckel-Mahan, K. L. et al. Circadian oscillation of hippocampal MAPK activity and cAMP: implications for memory persistence. Nature Neurosci. 11, 1074–1082 (2008)

    CAS  Article  Google Scholar 

  28. 28

    Vecsey, C. G. et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J. Neurosci. 27, 6128–6140 (2007)

    CAS  Article  Google Scholar 

  29. 29

    Lobban, M., Shakur, Y., Beattie, J. & Houslay, M. D. Identification of two splice variant forms of type-IVB cyclic AMP phosphodiesterase, DPD (rPDE-IVB1) and PDE-4 (rPDE-IVB2) in brain: selective localization in membrane and cytosolic compartments and differential expression in various brain regions. Biochem. J. 304, 399–406 (1994)

    CAS  Article  Google Scholar 

  30. 30

    Huston, E. et al. The cAMP-specific phosphodiesterase PDE4A5 is cleaved downstream of its SH3 interaction domain by caspase-3. Consequences for altered intracellular distribution. J. Biol. Chem. 275, 28063–28074 (2000)

    CAS  PubMed  Google Scholar 

  31. 31

    Ledoux, L., Sastre, J. P., Buda, C., Luppi, P. H. & Jouvet, M. Alterations in c-fos expression after different experimental procedures of sleep deprivation in the cat. Brain Res. 735, 108–118 (1996)

    CAS  Article  Google Scholar 

  32. 32

    Vecsey, C. G. et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J. Neurosci. 27, 6128–6140 (2007)

    CAS  Article  Google Scholar 

  33. 33

    Fanselow, M. S. Conditioned and unconditional components of post-shock freezing. Pavlov. J. Biol. Sci. 15, 177–182 (1980)

    CAS  PubMed  Google Scholar 

  34. 34

    Matthies, H. et al. Design of a multiple slice interface chamber and application for resolving the temporal pattern of CREB phosphorylation in hippocampal long-term potentiation. J. Neurosci. Methods 78, 173–179 (1997)

    CAS  Article  Google Scholar 

  35. 35

    Malleret, G. et al. Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell 104, 675–686 (2001)

    CAS  Article  Google Scholar 

  36. 36

    Abel, T. et al. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 88, 615–626 (1997)

    CAS  Article  Google Scholar 

  37. 37

    Huang, Y. Y. & Kandel, E. R. Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization. Learn. Mem. 1, 74–82 (1994)

    CAS  PubMed  Google Scholar 

  38. 38

    Woo, N. H., Duffy, S. N., Abel, T. & Nguyen, P. V. Temporal spacing of synaptic stimulation critically modulates the dependence of LTP on cyclic AMP-dependent protein kinase. Hippocampus 13, 293–300 (2003)

    CAS  Article  Google Scholar 

  39. 39

    Nguyen, P. V., Abel, T. & Kandel, E. R. Requirement of a critical period of transcription for induction of a late phase of LTP. Science 265, 1104–1107 (1994)

    ADS  CAS  Article  Google Scholar 

  40. 40

    Nguyen, P. V. & Kandel, E. R. Brief theta-burst stimulation induces a transcription-dependent late phase of LTP requiring cAMP in area CA1 of the mouse hippocampus. Learn. Mem. 4, 230–243 (1997)

    CAS  Article  Google Scholar 

  41. 41

    Daly, J. W., Padgett, W. & Seamon, K. B. Activation of cyclic AMP-generating systems in brain membranes and slices by the diterpene forskolin: augmentation of receptor-mediated responses. J. Neurochem. 38, 532–544 (1982)

    CAS  Article  Google Scholar 

  42. 42

    Beavo, J. A. et al. Effects of phosphodiesterase inhibitors on cyclic AMP levels and on lipolysis. Ann. NY Acad. Sci. 185, 129–136 (1971)

    ADS  CAS  Article  Google Scholar 

  43. 43

    Conti, M. & Beavo, J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu. Rev. Biochem. 76, 481–511 (2007)

    CAS  Article  Google Scholar 

  44. 44

    Wu, L. J. et al. Neurabin contributes to hippocampal long-term potentiation and contextual fear memory. PLoS One 3, e1407 (2008)

    ADS  Article  Google Scholar 

  45. 45

    Marchmont, R. J. & Houslay, M. D. Insulin trigger, cyclic AMP-dependent activation and phosphorylation of a plasma membrane cyclic AMP phosphodiesterase. Nature 286, 904–906 (1980)

    ADS  CAS  Article  Google Scholar 

  46. 46

    Lobban, M., Shakur, Y., Beattie, J. & Houslay, M. D. Identification of two splice variant forms of type-IVB cyclic AMP phosphodiesterase, DPD (rPDE-IVB1) and PDE-4 (rPDE-IVB2) in brain: selective localization in membrane and cytosolic compartments and differential expression in various brain regions. Biochem. J. 304, 399–406 (1994)

    CAS  Article  Google Scholar 

  47. 47

    Huston, E. et al. The cAMP-specific phosphodiesterase PDE4A5 is cleaved downstream of its SH3 interaction domain by caspase-3. Consequences for altered intracellular distribution. J. Biol. Chem. 275, 28063–28074 (2000)

    CAS  PubMed  Google Scholar 

  48. 48

    Lynch, M. J. et al. RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with beta arrestin to control the protein kinase A/AKAP79-mediated switching of the β2-adrenergic receptor to activation of ERK in HEK293B2 cells. J. Biol. Chem. 280, 33178–33189 (2005)

    CAS  Article  Google Scholar 

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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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Vecsey, C., Baillie, G., Jaganath, D. et al. Sleep deprivation impairs cAMP signalling in the hippocampus. Nature 461, 1122–1125 (2009). https://doi.org/10.1038/nature08488

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