Article | Published:

Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP

Nature Neuroscience volume 7, pages 635642 (2004) | Download Citation

Subjects

Abstract

Cyclic AMP is a positive regulator of synaptic plasticity and is required for several forms of hippocampus-dependent memory including recognition memory. The type I adenylyl cyclase, Adcy1 (also known as AC1), is crucial in memory formation because it couples Ca2+ to cyclic AMP increases in the hippocampus. Because Adcy1 is neurospecific, it is a potential pharmacological target for increasing cAMP specifically in the brain and for improving memory. We have generated transgenic mice that overexpress Adcy1 in the forebrain using the Camk2a (also known as α-CaMKII) promoter. These mice showed elevated long-term potentiation (LTP), increased memory for object recognition and slower rates of extinction for contextual memory. The increase in recognition memory and lower rates of contextual memory extinction may be due to enhanced extracellular signal–related kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling, which is elevated in mice that overexpress Adcy1.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Molecular bases of long-term memories: a question of persistence. Curr. Opin. Neurobiol. 12, 211–216 (2002).

  2. 2.

    , & Genetic approaches to molecular and cellular cognition: a focus on LTP and learning and memory. Annu. Rev. Genet. 36, 687–720 (2002).

  3. 3.

    , , & Targeting the CREB pathway for memory enhancers. Nat. Rev. Drug. Discov. 2, 267–277 (2003).

  4. 4.

    & Calmodulin-regulated adenylyl cyclases: cross-talk and plasticity in the central nervous system. Mol. Pharmacol. 63, 463–468 (2003).

  5. 5.

    & Molecular neurobiology of human cognition. Neuron 33, 845–848 (2002).

  6. 6.

    , , , & The amnesiac gene product is expressed in two neurons in the Drosophila brain that are critical for memory. Cell 103, 805–813 (2000).

  7. 7.

    , & Molecular analysis of cDNA clones and the corresponding genomic coding sequences of the Drosophila dunce+ gene, the structural gene for cAMP phosphodiesterase. Proc. Natl. Acad. Sci. USA 83, 9313–9317 (1986).

  8. 8.

    , & Loss of calcium/calmodulin responsiveness in adenylate cyclase of rutabaga, a Drosophila learning mutant. Cell 37, 205–215 (1984).

  9. 9.

    , & 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).

  10. 10.

    et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79, 49–58 (1994).

  11. 11.

    , , & CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 81, 107–115 (1995).

  12. 12.

    , , , & CREB1 encodes a nuclear activator, a repressor, and a cytoplasmic modulator that form a regulatory unit critical for long-term facilitation. Cell 95, 211–223 (1998).

  13. 13.

    , , , & Inhibitor of adenosine 3':5′-monophosphate-dependent protein kinase blocks presynaptic facilitation in Aplysia. J. Neurosci. 2, 1673–1681 (1982).

  14. 14.

    , & Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature 345, 718–721 (1990).

  15. 15.

    Hippocampal LTP and memory in mouse strains: is there evidence for a causal relationship? Hippocampus 12, 657–666 (2002).

  16. 16.

    & Synaptic plasticity: a molecular memory switch. Curr. Biol. 11, R788–791 (2001).

  17. 17.

    & New life in an old idea: the synaptic plasticity and memory hypothesis revisited. Hippocampus 12, 609–636 (2002).

  18. 18.

    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).

  19. 19.

    , , , & Postsynaptic cAMP pathway gates early LTP in hippocampal CA1 region. Neuron 15, 1403–1414 (1995).

  20. 20.

    , & Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science 260, 1661–1664 (1993).

  21. 21.

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

  22. 22.

    et al. Altered behavior and long-term potentiation in type I adenylyl cyclase mutant mice. Proc. Natl. Acad. Sci. USA 92, 220–224 (1995).

  23. 23.

    , & Cyclic AMP mediates a presynaptic form of LTP at cerebellar parallel fiber synapses. Neuron 16, 797–803 (1996).

  24. 24.

    , , & Type I adenylyl cyclase mutant mice have impaired mossy fiber long-term potentiation. J. Neurosci. 18, 3186–3194 (1998).

  25. 25.

    et al. A genetic test of the effects of mutations in PKA on mossy fiber LTP and its relation to spatial and contextual learning. Cell 83, 1211–1222 (1995).

  26. 26.

    & A macromolecular synthesis-dependent late phase of long-term potentiation requiring cAMP in the medial perforant pathway of rat hippocampal slices. J. Neurosci. 16, 3189–3198 (1996).

  27. 27.

    , & LTP in the lateral perforant path is beta-adrenergic receptor-dependent. Neuroreport 8, 719–724 (1997).

  28. 28.

    , , , & Impaired cerebellar long-term potentiation in type I adenylyl cyclase mutant mice. Neuron 20, 1199–1210 (1998).

  29. 29.

    et al. Removal of Giα1 constraints on adenylyl cyclase in the hippocampus enhances LTP and impairs memory formation. Neuron 41, 153–163 (2004).

  30. 30.

    et al. Associative learning disrupted by impaired Gs signaling in Drosophila mushroom bodies. Science 274, 2104–2107 (1996).

  31. 31.

    , , , & 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).

  32. 32.

    et al. A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. Proc. Natl. Acad. Sci. USA 100, 10518–10522 (2003).

  33. 33.

    , , , & Distribution of mRNA for the calmodulin-sensitive adenylate cyclase in rat brain: expression in areas associated with learning and memory. Neuron 6, 431–443 (1991).

  34. 34.

    et al. Control of memory formation through regulated expression of a CaMKII transgene. Science 274, 1678–1683 (1996).

  35. 35.

    , & Phosphorylation of rabphilin-3A by Ca2+/calmodulin-and cAMP-dependent protein kinases in vitro. J. Neurosci. 15, 2385–2395 (1995).

  36. 36.

    , , , & Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000).

  37. 37.

    et al. Characterization of protein kinase A and protein kinase C phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit using phosphorylation site-specific antibodies. J. Biol. Chem. 272, 5157–5166 (1997).

  38. 38.

    Exploratory behavior and reaction to novelty in rats with hippocampal perforant path systems disrupted. Behav. Neurosci. 102, 356–362 (1988).

  39. 39.

    & Impaired recognition memory in patients with lesions limited to the hippocampal formation. Behav. Neurosci. 111, 667–675 (1997).

  40. 40.

    et al. Neuronal calcium activates a Rap1 and B–Raf signaling pathway via the cyclic adenosine monophosphate-dependent protein kinase. J. Biol. Chem. 275, 3722–3728 (2000).

  41. 41.

    et al. Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21, 869–883 (1998).

  42. 42.

    , & Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 23, 11–14 (1999).

  43. 43.

    , , , & Memory extinction requires gene expression in rat hippocampus. Neurobiol. Learn. Mem. 79, 199–203 (2003).

  44. 44.

    , , , & The role of NMDA glutamate receptors, PKA, MAPK, and CAMKII in the hippocampus in extinction of conditioned fear. Hippocampus 13, 53–58 (2003).

  45. 45.

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

  46. 46.

    , , & Activity-dependent beta-adrenergic modulation of low frequency stimulation induced LTP in the hippocampal CA1 region. Neuron 17, 475–482 (1996).

  47. 47.

    et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).

  48. 48.

    & Inhibition of protein kinase A activity during conditioned taste aversion retrieval: interference with extinction or reconsolidation of a memory? Neuroreport 14, 405–407 (2003).

  49. 49.

    et al. Hippocampal level of neural specific adenylyl cyclase type I is decreased in Alzheimer's disease. Biochim. Biophys. Acta. 1535, 60–68 (2000).

  50. 50.

    & The genetic enhancement of memory. Cell. Mol. Life Sci. 60, 1–5 (2003).

Download references

Acknowledgements

We thank members of the Storm laboratory for suggestions and critical reading of the manuscript. The Camk2a promoter was from M. Mayford. This research was supported by the National Institutes of Health (NS 20498 to D.R.S., AG 00057 to H.W. and Public Health Service National Research Service Award 1F31NS042475-01 to V.V.P.).

Author information

Affiliations

  1. Department of Pharmacology, University of Washington, Box 357280, 1959 NE Pacific Street, Seattle, Washington 98195-7280, USA.

    • Hongbing Wang
    • , Gregory D Ferguson
    • , Victor V Pineda
    • , Paige E Cundiff
    •  & Daniel R Storm

Authors

  1. Search for Hongbing Wang in:

  2. Search for Gregory D Ferguson in:

  3. Search for Victor V Pineda in:

  4. Search for Paige E Cundiff in:

  5. Search for Daniel R Storm in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Daniel R Storm.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nn1248

Further reading