Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

Cyclic AMP-dependent protein kinase mediates ocular dominance shifts in cat visual cortex

Abstract

Visual experience during a critical period early in postnatal development can change connections within mammalian visual cortex. In a kitten at the peak of the critical period (P28–42), brief monocular deprivation can lead to complete dominance by the open eye, an ocular dominance shift. This process is driven by activity from the eyes, and depends on N-methyl-D-aspartate (NMDA) receptor activation. The components of the intracellular signaling cascade underlying these changes have not all been identified. Here we show that inhibition of protein kinase A (PKA) by Rp-8-Cl-cAMPS blocks ocular dominance shifts that occur following monocular deprivation early in the critical period. Inhibition of protein kinase G by Rp-8-Br-PET-cGMPS had no effect, indicating a specificity for the PKA pathway. Enhancement of PKA activity late in the critical period with Sp-8-Cl-cAMPS did not increase plasticity. PKA is a necessary component of the pathway leading to cortical plasticity during the critical period.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Inhibition of PKA blocks OD shifts.
Figure 2: Responses to visual stimulation are unchanged by inhibition of PKA.
Figure 3: Activation of CNG channels does not block OD shifts.
Figure 4: Inhibition of PKG does not block OD shifts.
Figure 5: Activation of PKA late in the critical period does not increase the size of OD shifts.

Similar content being viewed by others

References

  1. Dubnau, J. & Tully, T. Gene discovery in Drosophila: new insights for learning and memory. Annu. Rev. Neurosci. 21, 407–444 (1998).

    Article  CAS  Google Scholar 

  2. Abel, T. & Kandel, E. R. Positive and negative regulatory mechanisms that mediate long-term memory storage. Brain Res. Rev. 26, 360–378 (1998).

    Article  CAS  Google Scholar 

  3. Brandon E. P., Idzerda R. L. & McKnight, G. S. PKA isoforms, neural pathways, and behaviour: making the connection. Curr. Opin. Neurobiol. 7, 397–403 (1997).

    Article  CAS  Google Scholar 

  4. Weisskopf, M. G., Castillo, P. E., Zalutsky, R. A. & Nicoll, R. A. Mediation of hippocampal mossy fiber long-term potentiation by cyclic AMP. Science 265, 1878–1882 (1994).

    Article  CAS  Google Scholar 

  5. Wong, S. T. et al. Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP. Neuron 23, 787–798 (1999).

    Article  CAS  Google Scholar 

  6. Tzounopoulos, T., Janz, R., Südhof, T. C., Nicoll, R. A. & Malenka, R. C. A role for cAMP in long-term depression at hippocampal mossy fiber synapses. Neuron 21, 837–845 (1998).

    Article  CAS  Google Scholar 

  7. Dixon, D. & Atwood, H. L. Adenylate cyclase system is essential for long-term facilitation at the crayfish neuromuscular junction. J. Neurosci. 9, 4246–4252 (1989).

    Article  CAS  Google Scholar 

  8. Trudeau, L.-E., Emery, D. G. & Haydon, P. G. Direct modulation of the secretory machinery underlies PKA-dependent synaptic facilitation in hippocampal neurons. Neuron 17, 789–797 (1996).

    Article  CAS  Google Scholar 

  9. Chavez-Noriega, L. E. & Stevens, C. F. Increased transmitter release at excitatory synapses produced by direct activation of adenylate cyclase in rat hippocampal slices. J. Neurosci. 14, 310–317 (1994).

    Article  CAS  Google Scholar 

  10. Greengard, P., Jen, J., Nairn, A. C. & Stevens, C. F. Enhancement of the glutamate response by cAMP-dependent protein kinase in hippocampal neurons. Science 253, 1135–1138 (1991).

    Article  CAS  Google Scholar 

  11. Wang, L.-Y., Salter, M. W. & MacDonald, J. F. Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases. Science 253, 1132–1134 (1991).

    Article  CAS  Google Scholar 

  12. Montminy, M. Transcriptional regulation by cyclic AMP. Annu. Rev. Biochem. 66, 807–822 (1997).

    Article  CAS  Google Scholar 

  13. Wiesel, T. N. & Hubel, D. H. Single cell responses in striate cortex of kittens deprived of vision in one eye. J. Neurophysiol. 26, 1003–1017 (1963).

    Article  CAS  Google Scholar 

  14. Shatz, C. J. & Stryker, M. P. Ocular dominance in layer IV of the cat's visual cortex and the effects of monocular deprivation. J. Physiol. (Lond.) 281, 267–283 (1978).

    Article  CAS  Google Scholar 

  15. Bear, M. F., Kleinschmidt, A., Gu, Q. & Singer, W. Disruption of experience-dependent synaptic modifications in striate cortex by infusion of an NMDA receptor antagonist. J. Neurosci. 10, 909–925 (1990).

    Article  CAS  Google Scholar 

  16. Daw, N. W. et al. Injection of MK-801 affects ocular dominance shifts more than visual activity. J. Neurophysiol. 81, 204–215 (1999).

    Article  CAS  Google Scholar 

  17. Reid, S. N., Daw, N. W., Gregory, D. S. & Flavin, H. cAMP levels increased by activation of metabotropic glutamate receptors correlate with visual plasticity. J. Neurosci. 16, 7619–7626 (1996).

    Article  CAS  Google Scholar 

  18. Mower, G. D. The effect of dark rearing on the time course of the critical period in cat visual cortex. Dev. Brain Res. 58, 151–158 (1991).

    Article  CAS  Google Scholar 

  19. Hensch T. K. et al. Comparison of plasticity in vivo and in vitro in the developing visual cortex of normal and protein kinase A RIβ-deficient mice. J. Neurosci. 18, 2108–2117 (1998).

    Article  CAS  Google Scholar 

  20. Amieux, P. S. et al. Compensatory regulation of RIα protein levels in protein kinase A mutant mice. J. Biol. Chem. 272, 3993–3998 (1997).

    Article  CAS  Google Scholar 

  21. Dostmann, R. G. et al. Probing the cyclic nucleotide binding sites of cAMP-dependent protein kinases I and II with analogs of adenosine 3′,5′-cyclic phosphorothioates. J. Biol. Chem. 265, 10484–10491 (1990).

    CAS  PubMed  Google Scholar 

  22. Bois, P., Renaudon, B., Baruscotti, M., Lenfant, J. & DiFrancesco, D. Activation of f-channels by cAMP analogues in macropatches from rabbit sino-atrial node myocytes. J. Physiol. (Lond.) 501, 565–571 (1997).

    Article  CAS  Google Scholar 

  23. Kramer, R. H. & Tibbs, G. R. Antagonists of cyclic nucleotide-gated channels and molecular mapping of their site of action. J. Neurosci. 16, 1285–1293 (1996).

    Article  CAS  Google Scholar 

  24. Zhuo, M., Hu, Y., Schultz, C., Kandel, E. R. & Hawkins, R. D. Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation. Science 269, 635–639 (1994).

    Google Scholar 

  25. Gage, A. T., Reyes, M. & Stanton, P. K. Nitric-oxide-guanylyl-cyclase-dependent and -independent components of multiple forms of long-term synaptic depression. Hippocampus 7, 286–295 (1997).

    Article  CAS  Google Scholar 

  26. Butt, E., Pöhler, D., Genieser, H.-G., Huggins, J. P. & Bucher, B. Inhibition of cyclic GMP-dependent protein kinase-mediated effects by (Rp)-8-bromo-PET-cyclic GMPS. Br. J. Pharmacol. 116, 3110–3116 (1995).

    Article  CAS  Google Scholar 

  27. Wei, J.-Y., Cohen, E. D., Yan, Y.-Y., Geniesser, H.-G. & Barnstable, C. J. Identification of competitive antagonists of the rod photoreceptor cGMP-gated cation channel: β-phenyl-1, N2 –etheno-substituted cGMP analogues of probes of the cGMP binding site. Biochemistry 35, 16815–16823 (1996).

    Article  CAS  Google Scholar 

  28. Olson, C. R. & Freeman, R. D. Profile of the sensitive period for monocular deprivation in kittens. Exp. Brain Res. 39, 17–21 (1980).

    CAS  PubMed  Google Scholar 

  29. Reid, S. N., Daw, N. W., Czepita, D., Flavin, H. J. & Sessa, W. C. Inhibition of nitric oxide synthase does not alter ocular dominance shifts in kitten visual cortex. J. Physiol. (Lond.) 494, 511–517 (1996).

    Article  CAS  Google Scholar 

  30. Ruthazer, E. S., Gillespie, D. C., Dawson, T. M., Snyder, S. H. & Stryker, M. P. Inhibition of nitric oxide synthase does not prevent ocular dominance plasticity in kitten visual cortex. J. Physiol. (Lond.) 494, 519–527 (1996).

    Article  CAS  Google Scholar 

  31. Gordon, B., Daw, N. W. & Parkinson, D. The effect of age on binding of MK-801 in the cat visual cortex. Brain Res. Dev. Brain Res. 62, 61–67 (1991).

    Article  CAS  Google Scholar 

  32. Chetkovich, D. M., Gray, R., Johnston, D. & Sweatt, J. D. N-methyl-d-aspartate receptor activation increases cAMP levels and voltage gated Ca2+ channel activity in area CA1 of hippocampus. Proc. Natl. Acad. Sci. USA 88, 6467–6471 (1991).

    Article  CAS  Google Scholar 

  33. Roberson, E. D. & Sweatt, J. D. Transient activation of cyclic AMP-dependent protein kinase during hippocampal long-term potentiation. J. Biol. Chem. 271, 30436–30441 (1996).

    Article  CAS  Google Scholar 

  34. Bear, M. F. & Singer, W. Modulation of visual cortical plasticity by acetylcholine and noradrenaline. Nature 320, 172–176 (1986).

    Article  CAS  Google Scholar 

  35. Cerne, R., Rusin, K. I. & Randic, M. Enhancement of the N-methyl-d-aspartate response in spinal dorsal horn neurons by cAMP-dependent protein kinase. Neurosci. Lett. 161, 124–128 (1993).

    Article  CAS  Google Scholar 

  36. Blackstone, C., Murphy, T. H., Moss, S. J., Baraban, J. M. & Huganir, R. L. Cyclic AMP and synaptic activity dependent phosphorylation of AMPA-preferring glutamate receptors. J. Neurosci. 14, 7585–7593 (1994).

    Article  CAS  Google Scholar 

  37. Kano, M. & Konnerth, A. Potentiation of GABA-mediated currents by cAMP-dependent protein kinase. Neuroreport 3, 563–566 (1992).

    Article  CAS  Google Scholar 

  38. Poisbeau, P., Cheney, M. C., Browning, M. D. & Mody, I. Modulation of synaptic GABAA receptor function by PKA and PKC in adult hippocampal neurons. J. Neurosci. 19, 674–683 (1999).

    Article  CAS  Google Scholar 

  39. Pham, T. A., Impey, S., Storm, D. R. & Stryker, M. P. CRE-mediated gene transcription in neocortical neuronal plasticity during the developmental critical period. Neuron 22, 63–72 (1999).

    Article  CAS  Google Scholar 

  40. Mower, G. D. & Kaplan, I. V. Fos expression during the critical period in visual cortex: differences between normal and dark reared cats. Brain Res. Dev. Brain Res. 64, 264–269 (1999).

    CAS  Google Scholar 

  41. Imamura, K., Kasamatsu, T., Shirokawa, T. & Ohashi, T. Restoration of ocular dominance plasticity mediated by adenosine 3′,5′-monophosphate in adult visual cortex. Proc. R. Soc. (Lond.) B Biol. Sci. 266, 1507–1516 (1999).

    Article  CAS  Google Scholar 

  42. Bach, M. E. et al. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc. Natl. Acad. Sci. USA 96, 5280–5285 (1999).

    Article  CAS  Google Scholar 

  43. Hubel, D. H. & Wiesel, T. N. Receptive fields, binocular interaction and functional architecture in the cat's visual cortex. J. Physiol. (Lond.) 160, 106–154 (1962).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Public Service Grant # RO1 EY00053. Core facilities in the department are supported by Research to Prevent Blindness. The authors thank A. Roe and D. Mitchell for comments on the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christopher J. Beaver.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Beaver, C., Ji, Q., Fischer, Q. et al. Cyclic AMP-dependent protein kinase mediates ocular dominance shifts in cat visual cortex. Nat Neurosci 4, 159–163 (2001). https://doi.org/10.1038/83985

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/83985

This article is cited by

Search

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