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Calcium–calmodulin-dependent protein kinase IV is required for fear memory

Abstract

The ability to remember potential dangers in an environment is necessary to the survival of animals and humans. The cyclic AMP–responsive element binding protein (CREB) is a key transcription factor in synaptic plasticity and memory consolidation. We have found that in CaMKIV−/− mice—which are deficient in a component of the calcium–calmodulin-dependent protein kinase (CaMK) pathway, a major pathway of CREB activation—fear memory, but not persistent pain, was significantly reduced. CREB activation by fear conditioning and synaptic potentiation in the amygdala and cortical areas was reduced or blocked. We propose that cognitive memory related to a noxious shock can be disassociated from behavioral responses to tissue injury and inflammation.

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Figure 1: CaMKIV is required for fear memory but not behavioral responses to tissue injury.
Figure 2: Distribution of CaMKIV in selected areas of adult mouse brain.
Figure 3: CaMKIV contributes to activation of CREB by fear conditioning.
Figure 4: CaMKIV contributes to activation of CREB by fear conditioning.
Figure 5: Requirement of CaMKIV for amygdala and cortical synaptic potentiation.
Figure 6: CaMKIV is required for CaM translocation and activation of CREB in the hippocampus and amygdala.
Figure 7: CaMKIV contributes to CaM translocation and activation of CREB in three cortical areas.

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References

  1. Davis, M. The role of the amygdala in fear and anxiety. Annu. Rev. Neurosci. 15, 353–375 (1992).

    Article  CAS  Google Scholar 

  2. Davis, M., Walker, D. L. & Lee, Y. Amygdala and bed nucleus of the stria terminalis: differential roles in fear and anxiety measured with the acoustic startle reflex. Phil. Trans. R. Soc. Lond. Ser. B 352, 1675–1687 (1997).

    Article  CAS  Google Scholar 

  3. LeDoux, L. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).

    Article  CAS  Google Scholar 

  4. Maren, S. Neurobiology of Pavlovian fear conditioning. Annu. Rev. Neurosci. 24, 897–931 (2001).

    Article  CAS  Google Scholar 

  5. Frankland, P. W., O'Brien, C., Ohno, M., Kirkwood, A. & Silva, A. J. α-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature 411, 309–313 (2001).

    Article  CAS  Google Scholar 

  6. Bliss, T. V. P. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    Article  CAS  Google Scholar 

  7. McKernan, M. G. & Shinnick-Gallagher, P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390, 607–611 (1997).

    Article  CAS  Google Scholar 

  8. Rogan, M. T., Stäubli, U. V. & Ledoux, J. E. Fear conditioning induces associative long-term potentiation in the amygdala. Nature 390, 604–607 (1997).

    Article  CAS  Google Scholar 

  9. Maren, S. Long-term potentiation in the amygdala: a mechanism for emotional learning and memory. Trends Neurosci. 22, 561–567 (1999).

    Article  CAS  Google Scholar 

  10. Repa, J. C. et al. Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Nat. Neurosci. 4, 724–731 (2001).

    Article  CAS  Google Scholar 

  11. Schafe, G. E., Nader, K., Blair, H. T. & LeDoux, J. E. Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosci. 24, 540–546 (2001).

    Article  CAS  Google Scholar 

  12. Sheng, M., Thompson, M. A. & Greenberg, M. E. CREB: a Ca2+-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252, 1427–1430 (1991).

    Article  CAS  Google Scholar 

  13. Mayr, B. & Montminy, M. R. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rew. Mol. Cell Biol. 2, 599–609 (2001).

    Article  CAS  Google Scholar 

  14. Dash, P. K., Hochner, B. & Kandel, E. R. Injection of cAMP-responsive element into the nucleus of aplysia sensory neurons blocks long-term facilitation. Nature 345, 718–721 (1990).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Bourtchuladze, R., Frenguelli, B., Blendy, J., Cioffi, D., Schutz, G. & Silva, A. J. Deficient long-term memory in mice with a targeted mutation of the CaM-responsive element–binding protein. Cell 79, 59–68 (1994).

    Article  CAS  Google Scholar 

  17. Bartsch, D. et al. Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell 83, 979–992 (1995).

    Article  CAS  Google Scholar 

  18. Guzowski, J. F. & McGaugh, J. L. Antisense oligodeoxynucleotide–mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proc. Natl. Acad. Sci. USA 94, 2693–2698 (1997).

    Article  CAS  Google Scholar 

  19. Falls, W. A., Kogan, J. H., Silva, A. J., Willott, J. F., Carlson, S. & Turner, J. G. Fear-potentiation startle, but not prepulse inhibition of startle, impaired in CREB αδ−/− mutant mice. Behav. Neurosci. 114, 998–1004 (2000).

    Article  CAS  Google Scholar 

  20. Yin, J. C. P., Del Vecchio, M., Zhou, H. & Tully, T. CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 81, 107–115 (1995).

    Article  CAS  Google Scholar 

  21. Josselyn, S. A., Shi, C., Carlezon, W. A. Jr., Neve, R. L., Nestler, E. J. & Davis, M. Long-term memory is facilitated by cAMP response element–binding protein overexpression in the amygdala. J. Neurosci. 21, 2404–2412 (2001).

    Article  CAS  Google Scholar 

  22. Silva, A. J., Kogan, J. H., Frankland, P. W. & Kida, S. CREB and memory. Annu. Rev. Neurosci. 21, 127–148 (1998).

    Article  CAS  Google Scholar 

  23. Gonzalez, G. A. & Montminy, M. R. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59, 675–680 (1989).

    Article  CAS  Google Scholar 

  24. Bito, H., Deisseroth, K., & Tsien, R. W. CREB phosphorylation and dephosphorylation: a Ca2+- and stimulus duration–dependent switch for hippocampal gene expression. Cell 87, 1203–1214 (1996).

    Article  CAS  Google Scholar 

  25. Deisseroth, K., Bito, H. & Tsien, R. W. Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron 16, 89–101 (1996).

    Article  CAS  Google Scholar 

  26. Deisseroth, K., Heist, E. K. & Tsien, R.W. Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 392, 198–202 (1998).

    Article  CAS  Google Scholar 

  27. Soderling, T. R. CaM-kinase: modulator of synaptic plasticity. Curr. Opin. Neurobiol. 10, 375–380 (2000).

    Article  CAS  Google Scholar 

  28. Hardingham, G. E., Arnold, F. J. L. & Bading, H. Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Nat. Neurosci. 4, 261–267 (2001).

    Article  CAS  Google Scholar 

  29. West, A.E. et al. Calcium regulation of neuronal gene expression. Proc. Natl. Acad. Sci. USA 98, 11024–11031 (2001).

    Article  CAS  Google Scholar 

  30. Livingston, M. S., Sziber, P. P. & Quinn, W. G. Loss of calcium calmodulin responsiveness in adenylyl cyclase of rutabaga, a Drosophila learning mutant. Cell 37, 205–215 (1984).

    Article  Google Scholar 

  31. Foster, J. L., Guttman, J. J., Hall, L. M. & Rosen, O. M. Drosophila cAMP-dependent protein kinase. J. Biol. Chem. 259, 13049–13055 (1984).

    CAS  PubMed  Google Scholar 

  32. Abel, T., Nguyen, P. V., Barad, M., Deuel, T. A. S., Kandel. E. R. & Bourtchuladze, R. Genetic demonstration of a role for PKA in the late phase of LTP and the hippocampus-based long-term memory. Cell 88, 615–626 (1997).

    Article  CAS  Google Scholar 

  33. 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 

  34. Schafe, G. & LeDoux, J. E. Memory consolidation of auditory pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J. Neurosci. 20 (RC98), 1–5 (2000).

    Article  Google Scholar 

  35. Ho, N. et al. Impaired synaptic plasticity and cAMP response element–binding protein activation in Ca2+/calmodulin-dependent protein kinase type IV/Gr-deficient mice. J. Neurosci. 20, 6459–6472 (2000).

    Article  CAS  Google Scholar 

  36. Kang, H., Sun, L.D., Atkins, C.M., Soderling, T.R., Wilson, M.A. & Tonegawa, S. An important role of neural activity–dependent CaMKIV signaling in the consolidation of long-term memory. Cell 106, 771–783 (2001).

    Article  CAS  Google Scholar 

  37. Wei, F. et al. Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat. Neurosci. 4, 164–169 (2001).

    Article  CAS  Google Scholar 

  38. Kerchner, G. A. et al. Reply to “Do 'smart' mice feel more pain, or are they just better learners?” Nat. Neurosci. 4, 453–454 (2001).

    Article  Google Scholar 

  39. Impey, S., Smith, D. M., Obrietan, K., Donahue, R., Wade, C. & Storm, D.R. Stimulation of cAMP response element (CRE)–mediated transcription during contextual learning. Nat. Neurosci. 1, 595–601 (1998).

    Article  CAS  Google Scholar 

  40. Nakamura, Y., Okuno, S., Sato, F. & Fujisawa, H. An immunohistochemical study of Ca2+/calmodulin-dependent protein kinase IV in the rat central nervous system: light and electron microscopic observation. Neurosci. 68, 181–194 (1995).

    Article  CAS  Google Scholar 

  41. Schafe, G. E., Atkins, C. M., Swank, M. W., Bauer, E. P., Sweatt, J. D. & LeDoux, J. E. Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning. J. Neurosci 20, 8177–8187 (2000).

    Article  CAS  Google Scholar 

  42. Sah, P. & Nicoll, R.A. Mechanisms underlying potentiation of synaptic transmission in rat anterior cingulate cortex in vitro. J. Physiol. (Lond.) 433, 615–630 (1991).

    Article  CAS  Google Scholar 

  43. Liao, B., Paschal, B. M. & Luby-Phelps, K. Mechanism of Ca2+-dependent unclear accumulation of calmodulin. Proc. Natl. Acad. Sci. USA 96, 6217–6222 (1999).

    Article  CAS  Google Scholar 

  44. Teruel, M. N., Chen, W., Persechini, A. & Meyer, T. Differential codes for free Ca2+-calmodulin signals in nucleus and cytosol. Curr. Biol. 10, 86–94 (2000).

    Article  CAS  Google Scholar 

  45. Lisman, J., Malenka, R. C., Nicoll, R. A. & Malinow, R. Learning mechanisms: the case for CaM-KII. Science 276, 2001–2002 (1997).

    Article  CAS  Google Scholar 

  46. Silva, A. J., Paylor, R., Wehner, J. M. & Tonegawa, S. Impaired spatial learning in aα-calcium-calmodulin kinase II mutant mice. Science 257, 206–211 (1992).

    Article  CAS  Google Scholar 

  47. Bach, M. E., Hawkins, R. D., Osman, M., Kandel, E. R. & Mayford, M. Impairment of spatial but not contextual memory in CaMKII mutant mice with a selective loss of hippocampal LTP in the range of the theta frequency. Cell 81, 905–915 (1995).

    Article  CAS  Google Scholar 

  48. Giese, K. P., Fedorov, N. B., Filipkowski, R. K. & Silva, A. J. Autophosphorylation at Thr286 of the α calcium-calmodulin kinase II in LTP and learning. Science 279, 870–873 (1998).

    Article  CAS  Google Scholar 

  49. Tang, Y. P. et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 (1999).

    Article  CAS  Google Scholar 

  50. Franklin, K. B. J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates (Academic Press, New York, 1997).

    Google Scholar 

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Acknowledgements

Supported by grants from the National Institute of Neurological Disorders and Stroke 38680, the National Institute on Drug Abuse 10833, the McDonnell Center for Higher Brain Function and Alzheimer Disease Research Center at Washington University.

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Correspondence to Min Zhuo.

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Wei, F., Qiu, CS., Liauw, J. et al. Calcium–calmodulin-dependent protein kinase IV is required for fear memory. Nat Neurosci 5, 573–579 (2002). https://doi.org/10.1038/nn0602-855

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