Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep


Plastic changes occurring during wakefulness aid in the acquisition and consolidation of memories. For some memories, further consolidation requires sleep, but whether plastic processes during wakefulness and sleep differ is unclear. We show that, in rat cortex and hippocampus, GluR1-containing AMPA receptor (AMPAR) levels are high during wakefulness and low during sleep, and changes in the phosphorylation states of AMPARs, CamKII and GSK3β are consistent with synaptic potentiation during wakefulness and depression during sleep. Furthermore, slope and amplitude of cortical evoked responses increase after wakefulness, decrease after sleep and correlate with changes in slow-wave activity, a marker of sleep pressure. Changes in molecular and electrophysiological indicators of synaptic strength are largely independent of the time of day. Finally, cortical long-term potentiation can be easily induced after sleep, but not after wakefulness. Thus, wakefulness appears to be associated with net synaptic potentiation, whereas sleep may favor global synaptic depression, thereby preserving an overall balance of synaptic strength.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Molecular correlates of LTP/LTD in wakefulness and sleep.
Figure 2: Electrophysiological correlates of LTP and LTD in wakefulness and sleep.
Figure 3: Effect of behavioral state on the LFP responses.
Figure 4: Molecular correlates of LTP/LTD after enforced wakefulness.
Figure 5: Electrophysiological correlates of LTP/LTD after enforced wakefulness.
Figure 6: Relationship between LFP response slope and sleep slow-wave homeostasis.
Figure 7: Partial LTP occlusion after wakefulness.


  1. 1

    Steriade, M. Grouping of brain rhythms in corticothalamic systems. Neuroscience 137, 1087–1106 (2006).

    CAS  Article  Google Scholar 

  2. 2

    Hooks, B.M. & Chen, C. Distinct roles for spontaneous and visual activity in remodeling of the retinogeniculate synapse. Neuron 52, 281–291 (2006).

    CAS  Article  Google Scholar 

  3. 3

    Nicoll, R.A. & Malenka, R.C. Expression mechanisms underlying NMDA receptor–dependent long-term potentiation. Ann. NY Acad. Sci. 868, 515–525 (1999).

    CAS  Article  Google Scholar 

  4. 4

    Attwell, D. & Laughlin, S.B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21, 1133–1145 (2001).

    CAS  Article  Google Scholar 

  5. 5

    Tononi, G. & Cirelli, C. Sleep function and synaptic homeostasis. Sleep Med. Rev. 10, 49–62 (2006).

    Article  Google Scholar 

  6. 6

    Sejnowski, T.J. & Destexhe, A. Why do we sleep? Brain Res. 886, 208–223 (2000).

    CAS  Article  Google Scholar 

  7. 7

    Born, J., Rasch, B. & Gais, S. Sleep to remember. Neuroscientist 12, 410–424 (2006).

    PubMed  PubMed Central  Google Scholar 

  8. 8

    Malenka, R.C. & Bear, M.F. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Collingridge, G.L., Isaac, J.T. & Wang, Y.T. Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5, 952–962 (2004).

    CAS  Article  Google Scholar 

  10. 10

    Whitlock, J.R., Heynen, A.J., Shuler, M.G. & Bear, M.F. Learning induces long-term potentiation in the hippocampus. Science 313, 1093–1097 (2006).

    CAS  Article  Google Scholar 

  11. 11

    Clem, R.L. & Barth, A. Pathway-specific trafficking of native AMPARs by in vivo experience. Neuron 49, 663–670 (2006).

    CAS  Article  Google Scholar 

  12. 12

    Rumpel, S., LeDoux, J., Zador, A. & Malinow, R. Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005).

    CAS  Article  Google Scholar 

  13. 13

    Goel, A. et al. Cross-modal regulation of synaptic AMPA receptors in primary sensory cortices by visual experience. Nat. Neurosci. 9, 1001–1003 (2006).

    CAS  Article  Google Scholar 

  14. 14

    Hu, H. et al. Emotion enhances learning via norepinephrine regulation of AMPA receptor trafficking. Cell 131, 160–173 (2007).

    CAS  Article  Google Scholar 

  15. 15

    Heynen, A.J., Quinlan, E.M., Bae, D.C. & Bear, M.F. Bidirectional, activity-dependent regulation of glutamate receptors in the adult hippocampus in vivo. Neuron 28, 527–536 (2000).

    CAS  Article  Google Scholar 

  16. 16

    Cirelli, C. & Tononi, G. Differential expression of plasticity-related genes in waking and sleep and their regulation by the noradrenergic system. J. Neurosci. 20, 9187–9194 (2000).

    CAS  Article  Google Scholar 

  17. 17

    Kim, M.J., Dunah, A.W., Wang, Y.T. & Sheng, M. Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron 46, 745–760 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Lee, H.K., Barbarosie, M., Kameyama, K., Bear, M.F. & Huganir, R.L. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000).

    CAS  Article  Google Scholar 

  19. 19

    Lisman, J., Schulman, H. & Cline, H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat. Rev. Neurosci. 3, 175–190 (2002).

    CAS  Article  Google Scholar 

  20. 20

    Heynen, A.J. et al. Molecular mechanism for loss of visual cortical responsiveness following brief monocular deprivation. Nat. Neurosci. 6, 854–862 (2003).

    CAS  Article  Google Scholar 

  21. 21

    Steriade, M. & Hobson, J. Neuronal activity during the sleep-waking cycle. Prog. Neurobiol. 6, 155–376 (1976).

    CAS  Article  Google Scholar 

  22. 22

    Peineau, S. et al. LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron 53, 703–717 (2007).

    CAS  Article  Google Scholar 

  23. 23

    Kauer, J.A. & Malenka, R.C. LTP: AMPA receptors trading places. Nat. Neurosci. 9, 593–594 (2006).

    CAS  Article  Google Scholar 

  24. 24

    Plant, K. et al. Transient incorporation of native GluR2-lacking AMPA receptors during hippocampal long-term potentiation. Nat. Neurosci. 9, 602–604 (2006).

    CAS  Article  Google Scholar 

  25. 25

    Rall, W. Distinguishing theoretical synaptic potentials computed for different soma-dendritic distributions of synaptic input. J. Neurophysiol. 30, 1138–1168 (1967).

    CAS  Article  Google Scholar 

  26. 26

    Bliss, T.V. & Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. (Lond.) 232, 331–356 (1973).

    CAS  Article  Google Scholar 

  27. 27

    Glazewski, S., Herman, C., McKenna, M., Chapman, P.F. & Fox, K. Long-term potentiation in vivo in layers II/III of rat barrel cortex. Neuropharmacology 37, 581–592 (1998).

    CAS  Article  Google Scholar 

  28. 28

    Fox, C.J., Russell, K.I., Wang, Y.T. & Christie, B.R. Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo. Hippocampus 16, 907–915 (2006).

    CAS  Article  Google Scholar 

  29. 29

    Borbély, A.A. & Achermann, P. Sleep homeostasis and models of sleep regulation. in Principles and Practice of Sleep Medicine (eds. M.H. Kryger, T. Roth & W.C. Dement) 405–417 (W. B. Saunders, Philadelphia, 2005).

  30. 30

    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 

  31. 31

    Heynen, A.J. & Bear, M.F. Long-term potentiation of thalamocortical transmission in the adult visual cortex in vivo. J. Neurosci. 21, 9801–9813 (2001).

    CAS  Article  Google Scholar 

  32. 32

    Steriade, M.M. & McCarley, R. Brain Control of Wakefulness and Sleep, 728 (Springer, 2005).

    Google Scholar 

  33. 33

    Hall, R.D. & Borbely, A.A. Acoustically evoked potentials in the rat during sleep and waking. Exp. Brain Res. 11, 93–110 (1970).

    CAS  Article  Google Scholar 

  34. 34

    Moser, E., Mathiesen, I. & Andersen, P. Association between brain temperature and dentate field potentials in exploring and swimming rats. Science 259, 1324–1326 (1993).

    CAS  Article  Google Scholar 

  35. 35

    Cain, D.P., Hargreaves, E.L. & Boon, F. Brain temperature- and behavior-related changes in the dentate gyrus field potential during sleep, cold water immersion, radiant heating and urethane anesthesia. Brain Res. 658, 135–144 (1994).

    CAS  Article  Google Scholar 

  36. 36

    Esser, S.K., Hill, S.L. & Tononi, G. Sleep homeostasis, slow waves and cortical synchronization. I. Modeling the effects of synaptic strength on sleep slow waves. Sleep 30, 1617–1630 (2007).

    Article  Google Scholar 

  37. 37

    Huber, R., Ghilardi, M.F., Massimini, M. & Tononi, G. Local sleep and learning. Nature 430, 78–81 (2004).

    CAS  Article  Google Scholar 

  38. 38

    Huber, R. et al. Arm immobilization causes cortical plastic changes and locally decreases sleep slow wave activity. Nat. Neurosci. 9, 1169–1176 (2006).

    CAS  Article  Google Scholar 

  39. 39

    Vyazovskiy, V.V., Riedner, B.A., Cirelli, C. & Tononi, G. Sleep homeostasis and cortical synchronization. II. A local field potential study of sleep slow waves in the rat. Sleep 30, 1631–1642 (2007).

    Article  Google Scholar 

  40. 40

    Riedner, B.A. et al. Sleep homeostasis, slow waves and cortical synchronization. III. A high-density EEG study of sleep slow waves in humans. Sleep 30, 1643–1657 (2007).

    Article  Google Scholar 

  41. 41

    Czarnecki, A., Birtoli, B. & Ulrich, D. Cellular mechanisms of burst firing-mediated long-term depression in rat neocortical pyramidal cells. J. Physiol. (Lond.) 578, 471–479 (2007).

    CAS  Article  Google Scholar 

  42. 42

    Racine, R.J., Chapman, C.A., Trepel, C., Teskey, G.C. & Milgram, N.W. Post-activation potentiation in the neocortex. IV. Multiple sessions required for induction of long-term potentiation in the chronic preparation. Brain Res. 702, 87–93 (1995).

    CAS  Article  Google Scholar 

  43. 43

    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 

  44. 44

    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 

  45. 45

    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 

  46. 46

    Giuditta, A. et al. The sequential hypothesis of the function of sleep. Behav. Brain Res. 69, 157–166 (1995).

    CAS  Article  Google Scholar 

  47. 47

    Isomura, Y. et al. Integration and segregation of activity in entorhinal-hippocampal subregions by neocortical slow oscillations. Neuron 52, 871–882 (2006).

    CAS  Article  Google Scholar 

  48. 48

    Molle, M., Yeshenko, O., Marshall, L., Sara, S.J. & Born, J. Hippocampal sharp wave-ripples linked to slow oscillations in rat slow-wave sleep. J. Neurophysiol. 96, 62–70 (2006).

    Article  Google Scholar 

  49. 49

    Royer, S. & Pare, D. Conservation of total synaptic weight through balanced synaptic depression and potentiation. Nature 422, 518–522 (2003).

    CAS  Article  Google Scholar 

  50. 50

    Rioult-Pedotti, M.S., Friedman, D. & Donoghue, J.P. Learning-induced LTP in neocortex. Science 290, 533–536 (2000).

    CAS  Article  Google Scholar 

Download references


We thank M.F. Bear and his laboratory for help in optimizing the synaptoneurosome preparations. This work was supported by a US NIH Director's Pioneer award to G.T. and Swiss National Science Foundation grant PBZHB-106264 to V.V.V.

Author information




C.C. and M.P.-G. carried out the molecular experiments. V.V.V. performed the electrophysiological experiments and wrote part of the manuscript. U.F. participated in some of the electrophysiological experiments. C.C. and G.T. designed the experiments, coordinated the development of the study and wrote most of the manuscript.

Corresponding authors

Correspondence to Chiara Cirelli or Giulio Tononi.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Methods (PDF 900 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vyazovskiy, V., Cirelli, C., Pfister-Genskow, M. et al. Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep. Nat Neurosci 11, 200–208 (2008).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing