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:

The Drosophila DCO mutation suppresses age-related memory impairment without affecting lifespan

Nature Neuroscience volume 10, pages 478–484 (2007)Cite this article

Abstract

The study of age-related memory impairment (AMI) has been hindered by a lack of AMI-specific mutants. In a screen for such mutants in Drosophila melanogaster, we found that heterozygous mutations of DCO (DCO/+), which encodes the major catalytic subunit of cAMP-dependent protein kinase (PKA), delay AMI more than twofold without affecting lifespan or memory at early ages. AMI is restored when a DCO transgene is expressed in mushroom bodies, structures important for olfactory memory formation. Furthermore, increasing cAMP and PKA activity in mushroom bodies causes premature AMI, whereas reducing activity suppresses AMI. In Drosophila AMI consists of a specific reduction in memory dependent on the amnesiac (amn) gene. amn encodes putative neuropeptides that have been proposed to regulate cAMP levels in mushroom bodies. Notably, both the memory and AMI defects of amn mutants are restored in amn;DCO/+ double mutants, suggesting that AMI is caused by an age-related disruption of amn-dependent memory via PKA activity in mushroom bodies.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Suppression of AMI in DCO/+ mutants.
Figure 2: Memory retention is relatively unaffected by age in DCO/+ mutants.
Figure 3: DCO/+ mutants delay AMI by a process distinct from lifespan extension.
Figure 4: Expression of DCO in the mushroom bodies restores AMI in DCO/+ mutants.
Figure 5: Regulation of AMI by PKA activity in the mushroom bodies.
Figure 6: DCO expression, PKA activity and cAMP levels remain unchanged by fly aging.
Figure 7: Genetic interaction between amn and DCO.

Similar content being viewed by others

References

  1. Rosenzweig, E.S. & Barnes, C.A. Impact of aging on hippocampal function: plasticity, network dynamics, and cognition. Prog. Neurobiol. 69, 143–179 (2003).

    Article  CAS  Google Scholar 

  2. Foster, T.C. Regulation of synaptic plasticity in memory and memory decline with aging. Prog. Brain Res. 138, 283–303 (2002).

    Article  CAS  Google Scholar 

  3. Horiuchi, J. & Saitoe, M. Can flies shed light on our own age-related memory impairment? Ageing Res. Rev. 4, 83–101 (2005).

    Article  Google Scholar 

  4. Saitoe, M., Horiuchi, J., Tamura, T. & Ito, N. Drosophila as a novel animal model for studying the genetics of age-related memory impairment. Rev. Neurosci. 16, 137–149 (2005).

    Article  CAS  Google Scholar 

  5. Kim, D.W. & Choi, J.H. Effects of age and dietary restriction on animal model SAMP8 mice with learning and memory impairments. J. Nutr. Health Aging 4, 233–238 (2000).

    CAS  PubMed  Google Scholar 

  6. Kinney, B.A., Meliska, C.J., Steger, R.W. & Bartke, A. Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters. Horm. Behav. 39, 277–284 (2001).

    Article  CAS  Google Scholar 

  7. Liu, R. et al. Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics. Proc. Natl. Acad. Sci. USA 100, 8526–8531 (2003).

    Article  CAS  Google Scholar 

  8. Sampayo, J.N., Gill, M.S. & Lithgow, G.J. Oxidative stress and aging—the use of superoxide dismutase/catalase mimetics to extend lifespan. Biochem. Soc. Trans. 31, 1305–1307 (2003).

    Article  CAS  Google Scholar 

  9. Markowska, A.L. Life-long diet restriction failed to retard cognitive aging in Fischer-344 rats. Neurobiol. Aging 20, 177–189 (1999).

    Article  CAS  Google Scholar 

  10. Yanai, S., Okaichi, Y. & Okaichi, H. Long-term dietary restriction causes negative effects on cognitive functions in rats. Neurobiol. Aging 25, 325–332 (2004).

    Article  Google Scholar 

  11. Lupien, S.B., Bluhm, E.J. & Ishii, D.N. Systemic insulin-like growth factor-I administration prevents cognitive impairment in diabetic rats, and brain IGF regulates learning/memory in normal adult rats. J. Neurosci. Res. 74, 512–523 (2003).

    Article  CAS  Google Scholar 

  12. Markowska, A.L., Mooney, M. & Sonntag, W.E. Insulin-like growth factor-1 ameliorates age-related behavioral deficits. Neuroscience 87, 559–569 (1998).

    Article  CAS  Google Scholar 

  13. Sonntag, W.E., Ramsey, M. & Carter, C.S. Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging. Ageing Res. Rev. 4, 195–212 (2005).

    Article  CAS  Google Scholar 

  14. Tully, T. et al. A return to genetic dissection of memory in Drosophila. Cold Spring Harb. Symp. Quant. Biol. 61, 207–218 (1996).

    Article  CAS  Google Scholar 

  15. Tamura, T. et al. Aging specifically impairs amnesiac-dependent memory in Drosophila. Neuron 40, 1003–1011 (2003).

    Article  CAS  Google Scholar 

  16. Waddell, S., Armstrong, J.D., Kitamoto, T., Kaiser, K. & Quinn, W.G. The amnesiac gene product is expressed in two neurons in the Drosophila brain that are critical for memory. Cell 103, 805–813 (2000).

    Article  CAS  Google Scholar 

  17. Heisenberg, M. Mushroom body memoir: from maps to models. Nat. Rev. Neurosci. 4, 266–275 (2003).

    Article  CAS  Google Scholar 

  18. Skoulakis, E.M., Kalderon, D. & Davis, R.L. Preferential expression in mushroom bodies of the catalytic subunit of protein kinase A and its role in learning and memory. Neuron 11, 197–208 (1993).

    Article  CAS  Google Scholar 

  19. Grotewiel, M.S., Beck, C.D., Wu, K.H., Zhu, X.R. & Davis, R.L. Integrin-mediated short-term memory in Drosophila. Nature 391, 455–460 (1998).

    Article  CAS  Google Scholar 

  20. Skoulakis, E.M. & Davis, R.L. Olfactory learning deficits in mutants for leonardo, a Drosophila gene encoding a 14-3-3 protein. Neuron 17, 931–944 (1996).

    Article  CAS  Google Scholar 

  21. Tully, T. & Quinn, W.G. Classical conditioning and retention in normal and mutant Drosophila melanogaster. J. Comp. Physiol. A 157, 263–277 (1985).

    Article  CAS  Google Scholar 

  22. Lane, M.E. & Kalderon, D. Genetic investigation of cAMP-dependent protein kinase function in Drosophila development. Genes Dev. 7, 1229–1243 (1993).

    Article  CAS  Google Scholar 

  23. Drain, P., Folkers, E. & Quinn, W.G. cAMP-dependent protein kinase and the disruption of learning in transgenic flies. Neuron 6, 71–82 (1991).

    Article  CAS  Google Scholar 

  24. Li, W., Tully, T. & Kalderon, D. Effects of a conditional Drosophila PKA mutant on olfactory learning and memory. Learn. Mem. 2, 320–333 (1996).

    Article  CAS  Google Scholar 

  25. Crittenden, J.R., Skoulakis, E.M., Han, K.A., Kalderon, D. & Davis, R.L. Tripartite mushroom body architecture revealed by antigenic markers. Learn. Mem. 5, 38–51 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Brand, A.H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993).

    CAS  PubMed  Google Scholar 

  27. Kiger, J.A., Jr. & O'Shea, C. Genetic evidence for a protein kinase A/cubitus interruptus complex that facilitates processing of cubitus interruptus in Drosophila. Genetics 158, 1157–1166 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Nighorn, A., Healy, M.J. & Davis, R.L. The cyclic AMP phosphodiesterase encoded by the Drosophila dunce gene is concentrated in the mushroom body neuropil. Neuron 6, 455–467 (1991).

    Article  CAS  Google Scholar 

  29. Kiger, J.A., Jr., Eklund, J.L., Younger, S.H. & O'Kane, C.J. Transgenic inhibitors identify two roles for protein kinase A in Drosophila development. Genetics 152, 281–290 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mao, Z., Roman, G., Zong, L. & Davis, R.L. Pharmacogenetic rescue in time and space of the rutabaga memory impairment by using Gene-Switch. Proc. Natl. Acad. Sci. USA 101, 198–203 (2004).

    Article  CAS  Google Scholar 

  31. Osterwalder, T., Yoon, K.S., White, B.H. & Keshishian, H. A conditional tissue-specific transgene expression system using inducible GAL4. Proc. Natl. Acad. Sci. USA 98, 12596–12601 (2001).

    Article  CAS  Google Scholar 

  32. Feany, M.B. & Quinn, W.G. A neuropeptide gene defined by the Drosophila memory mutant amnesiac. Science 268, 869–873 (1995).

    Article  CAS  Google Scholar 

  33. Deyo, R.A., Straube, K.T. & Disterhoft, J.F. Nimodipine facilitates associative learning in aging rabbits. Science 243, 809–811 (1989).

    Article  CAS  Google Scholar 

  34. Straube, K.T., Deyo, R.A., Moyer, J.R., Jr. & Disterhoft, J.F. Dietary nimodipine improves associative learning in aging rabbits. Neurobiol. Aging 11, 659–661 (1990).

    Article  CAS  Google Scholar 

  35. Thibault, O. & Landfield, P.W. Increase in single L-type calcium channels in hippocampal neurons during aging. Science 272, 1017–1020 (1996).

    Article  CAS  Google Scholar 

  36. Thibault, O., Hadley, R. & Landfield, P.W. Elevated postsynaptic [Ca2+]i and L-type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity. J. Neurosci. 21, 9744–9756 (2001).

    Article  CAS  Google Scholar 

  37. Davare, M.A. & Hell, J.W. Increased phosphorylation of the neuronal L-type Ca2+ channel Cav1.2 during aging. Proc. Natl. Acad. Sci. USA 100, 16018–16023 (2003).

    Article  CAS  Google Scholar 

  38. Morrison, J.H. & Hof, P.R. Life and death of neurons in the aging brain. Science 278, 412–419 (1997).

    Article  CAS  Google Scholar 

  39. Liu, S.J. et al. Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain. J. Biol. Chem. 279, 50078–50088 (2004).

    Article  CAS  Google Scholar 

  40. Bhattacharya, A., Lakhman, S.S. & Singh, S. Modulation of L-type calcium channels in Drosophila via a pituitary adenylyl cyclase–activating polypeptide (PACAP)–mediated pathway. J. Biol. Chem. 279, 37291–37297 (2004).

    Article  CAS  Google Scholar 

  41. Zhong, Y. Mediation of PACAP-like neuropeptide transmission by coactivation of Ras/Raf and cAMP signal transduction pathways in Drosophila. Nature 375, 588–592 (1995).

    Article  CAS  Google Scholar 

  42. Rosay, P., Armstrong, J.D., Wang, Z. & Kaiser, K. Synchronized neural activity in the Drosophila memory centers and its modulation by amnesiac. Neuron 30, 759–770 (2001).

    Article  CAS  Google Scholar 

  43. Han, P.L., Levin, L.R., Reed, R.R. & Davis, R.L. Preferential expression of the Drosophila rutabaga gene in mushroom bodies, neural centers for learning in insects. Neuron 9, 619–627 (1992).

    Article  CAS  Google Scholar 

  44. Ramos, B.P. et al. Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron 40, 835–845 (2003).

    Article  CAS  Google Scholar 

  45. 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 

  46. Barad, M., Bourtchouladze, R., Winder, D.G., Golan, H. & Kandel, E. Rolipram, a type IV–specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc. Natl. Acad. Sci. USA 95, 15020–15025 (1998).

    Article  CAS  Google Scholar 

  47. Frey, U., Huang, Y.Y. & Kandel, E.R. Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science 260, 1661–1664 (1993).

    Article  CAS  Google Scholar 

  48. Dura, J.M., Preat, T. & Tully, T. Identification of linotte, a new gene affecting learning and memory in Drosophila melanogaster. J. Neurogenet. 9, 1–14 (1993).

    Article  CAS  Google Scholar 

  49. Tully, T., Preat, T., Boynton, S.C. & Del Vecchio, M. Genetic dissection of consolidated memory in Drosophila. Cell 79, 35–47 (1994).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Kalderon for DCO mutants and antibody to DCO, J.D. Armstrong and L.C Griffith for enhancer GAL4 lines, J. Kiger for the UAS-PKAc and PKI strains, R. Davis for the MB-Switch strain and A. Hattori for help with statistical analyses. This work was funded by a Grant-in-Aid for Scientific Research (B) (14380374) and Scientific Research on Priority Areas–Integrative Brain Research (17021052) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and The Uehara Memorial Foundation.

Author information

Author notes

  1. Daisuke Yamazaki and Junjiro Horiuchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Tokyo Metropolitan Institute for Neuroscience, Fuchu, 183-8526, Tokyo, Japan

    Daisuke Yamazaki, Junjiro Horiuchi, Yasuko Nakagami, Shintaro Nagano, Takuya Tamura & Minoru Saitoe

  2. Department of Biological Science, Tokyo Metropolitan University, Hachioji, 192-0397, Tokyo, Japan

    Daisuke Yamazaki & Shintaro Nagano

  3. Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, 278-8510, Chiba, Japan

    Yasuko Nakagami

  4. Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, 113-8510, Tokyo, Japan

    Takuya Tamura

Authors
  1. Daisuke Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junjiro Horiuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasuko Nakagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shintaro Nagano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takuya Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Minoru Saitoe
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.Y and J.H performed most of the experiments and analyzing the data. Y.N. performed experiments shown in Figure 5 and Supplementary Figure 2 with M.S. S.N. performed experiments shown in Supplementary Figure 1. T.T. performed initial behavioral screening shown in Figure 1. M.S. designed the research project and wrote the manuscript together with J.H.

Corresponding author

Correspondence to Minoru Saitoe.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

P-GAL4 expression patterns in adult brains. (PDF 2673 kb)

Supplementary Fig. 2

Induction of PKI by feeding RU486. (PDF 185 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamazaki, D., Horiuchi, J., Nakagami, Y. et al. The Drosophila DCO mutation suppresses age-related memory impairment without affecting lifespan. Nat Neurosci 10, 478–484 (2007). https://doi.org/10.1038/nn1863

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1863

This article is cited by

Search

Advanced 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