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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Jan 3;92(1):220–224. doi: 10.1073/pnas.92.1.220

Altered behavior and long-term potentiation in type I adenylyl cyclase mutant mice.

Z L Wu 1, S A Thomas 1, E C Villacres 1, Z Xia 1, M L Simmons 1, C Chavkin 1, R D Palmiter 1, D R Storm 1
PMCID: PMC42849  PMID: 7816821

Abstract

The murine Ca(2+)-stimulated adenylyl cyclase (type I) (EC 4.6.1.1), which is expressed predominantly in brain, was inactivated by targeted mutagenesis. Ca(2+)-stimulated adenylyl cyclase activity was reduced 40-60% in the hippocampus, neocortex, and cerebellum. Long-term potentiation in the CA1 region of the hippocampus from mutants was perturbed relative to controls. Both the initial slope and maximum extent of changes in synaptic response were reduced. Although mutant mice learned to find a hidden platform in the Morris water task normally, they did not display a preference for the region where the platform had been when it was removed. These results indicate that disruption of the gene for the type I adenylyl cyclase produces changes in behavior and that the cAMP signal transduction pathway may play an important role in synaptic plasticity.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abeliovich A., Chen C., Goda Y., Silva A. J., Stevens C. F., Tonegawa S. Modified hippocampal long-term potentiation in PKC gamma-mutant mice. Cell. 1993 Dec 31;75(7):1253–1262. doi: 10.1016/0092-8674(93)90613-u. [DOI] [PubMed] [Google Scholar]
  2. Abeliovich A., Paylor R., Chen C., Kim J. J., Wehner J. M., Tonegawa S. PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning. Cell. 1993 Dec 31;75(7):1263–1271. doi: 10.1016/0092-8674(93)90614-v. [DOI] [PubMed] [Google Scholar]
  3. Abrams T. W., Karl K. A., Kandel E. R. Biochemical studies of stimulus convergence during classical conditioning in Aplysia: dual regulation of adenylate cyclase by Ca2+/calmodulin and transmitter. J Neurosci. 1991 Sep;11(9):2655–2665. doi: 10.1523/JNEUROSCI.11-09-02655.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bacskai B. J., Hochner B., Mahaut-Smith M., Adams S. R., Kaang B. K., Kandel E. R., Tsien R. Y. Spatially resolved dynamics of cAMP and protein kinase A subunits in Aplysia sensory neurons. Science. 1993 Apr 9;260(5105):222–226. doi: 10.1126/science.7682336. [DOI] [PubMed] [Google Scholar]
  5. Cali J. J., Zwaagstra J. C., Mons N., Cooper D. M., Krupinski J. Type VIII adenylyl cyclase. A Ca2+/calmodulin-stimulated enzyme expressed in discrete regions of rat brain. J Biol Chem. 1994 Apr 22;269(16):12190–12195. [PubMed] [Google Scholar]
  6. Capecchi M. R. Altering the genome by homologous recombination. Science. 1989 Jun 16;244(4910):1288–1292. doi: 10.1126/science.2660260. [DOI] [PubMed] [Google Scholar]
  7. Choi E. J., Wong S. T., Dittman A. H., Storm D. R. Phorbol ester stimulation of the type I and type III adenylyl cyclases in whole cells. Biochemistry. 1993 Mar 2;32(8):1891–1894. doi: 10.1021/bi00059a001. [DOI] [PubMed] [Google Scholar]
  8. Choi E. J., Wong S. T., Hinds T. R., Storm D. R. Calcium and muscarinic agonist stimulation of type I adenylylcyclase in whole cells. J Biol Chem. 1992 Jun 25;267(18):12440–12442. [PubMed] [Google Scholar]
  9. Choi E. J., Xia Z., Villacres E. C., Storm D. R. The regulatory diversity of the mammalian adenylyl cyclases. Curr Opin Cell Biol. 1993 Apr;5(2):269–273. doi: 10.1016/0955-0674(93)90115-7. [DOI] [PubMed] [Google Scholar]
  10. Davis S., Butcher S. P., Morris R. G. The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. J Neurosci. 1992 Jan;12(1):21–34. doi: 10.1523/JNEUROSCI.12-01-00021.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dittman A. H., Weber J. P., Hinds T. R., Choi E. J., Migeon J. C., Nathanson N. M., Storm D. R. A novel mechanism for coupling of m4 muscarinic acetylcholine receptors to calmodulin-sensitive adenylyl cyclases: crossover from G protein-coupled inhibition to stimulation. Biochemistry. 1994 Feb 1;33(4):943–951. doi: 10.1021/bi00170a013. [DOI] [PubMed] [Google Scholar]
  12. Frey U., Huang Y. Y., Kandel E. R. Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science. 1993 Jun 11;260(5114):1661–1664. doi: 10.1126/science.8389057. [DOI] [PubMed] [Google Scholar]
  13. Gallo V., Ciotti M. T., Coletti A., Aloisi F., Levi G. Selective release of glutamate from cerebellar granule cells differentiating in culture. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7919–7923. doi: 10.1073/pnas.79.24.7919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Grant S. G., O'Dell T. J., Karl K. A., Stein P. L., Soriano P., Kandel E. R. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science. 1992 Dec 18;258(5090):1903–1910. doi: 10.1126/science.1361685. [DOI] [PubMed] [Google Scholar]
  15. Hagiwara M., Brindle P., Harootunian A., Armstrong R., Rivier J., Vale W., Tsien R., Montminy M. R. Coupling of hormonal stimulation and transcription via the cyclic AMP-responsive factor CREB is rate limited by nuclear entry of protein kinase A. Mol Cell Biol. 1993 Aug;13(8):4852–4859. doi: 10.1128/mcb.13.8.4852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hopkins W. F., Johnston D. Noradrenergic enhancement of long-term potentiation at mossy fiber synapses in the hippocampus. J Neurophysiol. 1988 Feb;59(2):667–687. doi: 10.1152/jn.1988.59.2.667. [DOI] [PubMed] [Google Scholar]
  17. Kaang B. K., Kandel E. R., Grant S. G. Activation of cAMP-responsive genes by stimuli that produce long-term facilitation in Aplysia sensory neurons. Neuron. 1993 Mar;10(3):427–435. doi: 10.1016/0896-6273(93)90331-k. [DOI] [PubMed] [Google Scholar]
  18. Levin L. R., Han P. L., Hwang P. M., Feinstein P. G., Davis R. L., Reed R. R. The Drosophila learning and memory gene rutabaga encodes a Ca2+/Calmodulin-responsive adenylyl cyclase. Cell. 1992 Feb 7;68(3):479–489. doi: 10.1016/0092-8674(92)90185-f. [DOI] [PubMed] [Google Scholar]
  19. Linden D. J., Routtenberg A. The role of protein kinase C in long-term potentiation: a testable model. Brain Res Brain Res Rev. 1989 Jul-Sep;14(3):279–296. doi: 10.1016/0165-0173(89)90004-0. [DOI] [PubMed] [Google Scholar]
  20. Livingstone M. S. Genetic dissection of Drosophila adenylate cyclase. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5992–5996. doi: 10.1073/pnas.82.17.5992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Livingstone M. S., Sziber P. P., Quinn W. G. Loss of calcium/calmodulin responsiveness in adenylate cyclase of rutabaga, a Drosophila learning mutant. Cell. 1984 May;37(1):205–215. doi: 10.1016/0092-8674(84)90316-7. [DOI] [PubMed] [Google Scholar]
  22. McMahon A. P., Bradley A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell. 1990 Sep 21;62(6):1073–1085. doi: 10.1016/0092-8674(90)90385-r. [DOI] [PubMed] [Google Scholar]
  23. Meyer T. E., Habener J. F. Cyclic adenosine 3',5'-monophosphate response element binding protein (CREB) and related transcription-activating deoxyribonucleic acid-binding proteins. Endocr Rev. 1993 Jun;14(3):269–290. doi: 10.1210/edrv-14-3-269. [DOI] [PubMed] [Google Scholar]
  24. Morris R. G. M., Schenk F., Tweedie F., Jarrard L. E. Ibotenate Lesions of Hippocampus and/or Subiculum: Dissociating Components of Allocentric Spatial Learning. Eur J Neurosci. 1990;2(12):1016–1028. doi: 10.1111/j.1460-9568.1990.tb00014.x. [DOI] [PubMed] [Google Scholar]
  25. 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. 1986 Feb 27-Mar 5Nature. 319(6056):774–776. doi: 10.1038/319774a0. [DOI] [PubMed] [Google Scholar]
  26. Morris R. G., Garrud P., Rawlins J. N., O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982 Jun 24;297(5868):681–683. doi: 10.1038/297681a0. [DOI] [PubMed] [Google Scholar]
  27. Morris R. G. Toward a representational hypothesis of the role of hippocampal synaptic plasticity in spatial and other forms of learning. Cold Spring Harb Symp Quant Biol. 1990;55:161–173. doi: 10.1101/sqb.1990.055.01.019. [DOI] [PubMed] [Google Scholar]
  28. Nigg E. A., Hilz H., Eppenberger H. M., Dutly F. Rapid and reversible translocation of the catalytic subunit of cAMP-dependent protein kinase type II from the Golgi complex to the nucleus. EMBO J. 1985 Nov;4(11):2801–2806. doi: 10.1002/j.1460-2075.1985.tb04006.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Silva A. J., Paylor R., Wehner J. M., Tonegawa S. Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992 Jul 10;257(5067):206–211. doi: 10.1126/science.1321493. [DOI] [PubMed] [Google Scholar]
  30. Silva A. J., Stevens C. F., Tonegawa S., Wang Y. Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992 Jul 10;257(5067):201–206. doi: 10.1126/science.1378648. [DOI] [PubMed] [Google Scholar]
  31. Slack J. R., Pockett S. Cyclic AMP induces long-term increase in synaptic efficacy in CA1 region of rat hippocampus. Neurosci Lett. 1991 Sep 2;130(1):69–72. doi: 10.1016/0304-3940(91)90229-m. [DOI] [PubMed] [Google Scholar]
  32. Soriano P., Montgomery C., Geske R., Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 1991 Feb 22;64(4):693–702. doi: 10.1016/0092-8674(91)90499-o. [DOI] [PubMed] [Google Scholar]
  33. Tang W. J., Gilman A. G. Adenylyl cyclases. Cell. 1992 Sep 18;70(6):869–872. doi: 10.1016/0092-8674(92)90236-6. [DOI] [PubMed] [Google Scholar]
  34. Wayman G. A., Impey S., Wu Z., Kindsvogel W., Prichard L., Storm D. R. Synergistic activation of the type I adenylyl cyclase by Ca2+ and Gs-coupled receptors in vivo. J Biol Chem. 1994 Oct 14;269(41):25400–25405. [PubMed] [Google Scholar]
  35. Wu Z., Wong S. T., Storms D. R. Modification of the calcium and calmodulin sensitivity of the type I adenylyl cyclase by mutagenesis of its calmodulin binding domain. J Biol Chem. 1993 Nov 15;268(32):23766–23768. [PubMed] [Google Scholar]
  36. Xia Z. G., Refsdal C. D., Merchant K. M., Dorsa D. M., Storm D. R. Distribution of mRNA for the calmodulin-sensitive adenylate cyclase in rat brain: expression in areas associated with learning and memory. Neuron. 1991 Mar;6(3):431–443. doi: 10.1016/0896-6273(91)90251-t. [DOI] [PubMed] [Google Scholar]
  37. Xia Z., Choi E. J., Wang F., Blazynski C., Storm D. R. Type I calmodulin-sensitive adenylyl cyclase is neural specific. J Neurochem. 1993 Jan;60(1):305–311. doi: 10.1111/j.1471-4159.1993.tb05852.x. [DOI] [PubMed] [Google Scholar]

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