Abstract
Cortical plasticity seems to be critical for the establishment of permanent memory traces1,2,3. Little is known, however, about the molecular and cellular processes that support consolidation of memories in cortical networks4,5. Here we show that mice heterozygous for a null mutation of α-calcium-calmodulin kinase II (α-CaMKII+/-) show normal learning and memory 1–3 days after training in two hippocampus-dependent tasks. However, their memory is severely impaired at longer retention delays (10–50 days). Consistent with this, we found that α-CaMKII+/- mice have impaired cortical, but not hippocampal, long-term potentiation. Our results represent a first step in unveiling the molecular and cellular mechanisms underlying the establishment of permanent memories, and they indicate that α-CaMKII may modulate the synaptic events required for the consolidation of memory traces in cortical networks.
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References
Squire, L. R. & Alvarez, P. Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr. Opin. Neurobiol. 5, 169–177 (1995).
Graham, K. S., Patterson, K. & Hodges, J. R. Episodic memory: new insights from the study of semantic dementia. Curr. Opin. Neurobiol. 9, 245–250 (1999).
McClelland, J. L., McNaughton, B. L. & O'Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol. Rev. 102, 419–457 (1995).
Dudai, Y. Consolidation: fragility on the road to the engram. Neuron 17, 367–370 (1996).
McGaugh, J. L. Memory—a century of consolidation. Science 287, 248–251 (2000).
Silva, A. J., Paylor, R., Wehner, J. M. & Tonegawa, S. Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science 257, 206–211 (1992).
Silva, A. J. et al. Impaired learning in mice with abnormal short-lived plasticity. Curr. Biol. 6, 1509–1518 (1996).
Glazewski, S., Chen, C. M., Silva, A. & Fox, K. Requirement for alpha-CaMKII in experience-dependent plasticity of the barrel cortex. Science 272, 421–423 (1996).
Gordon, J. A., Cioffi, D., Silva, A. J. & Stryker, M. P. Deficient plasticity in the primary visual cortex of alpha-calcium/calmodulin-dependent protein kinase II mutant mice. Neuron 17, 491–496 (1996).
Kim, J. J. & Fanselow, M. S. Modality-specific retrograde amnesia of fear. Science 256, 675–677 (1992).
Frankland, P. W., Cestari, V., Filipkowski, R. K., McDonald, R. J. & Silva, A. J. The dorsal hippocampus is essential for context discrimination but not for contextual conditioning. Behav. Neurosci. 112, 863–874 (1998).
Anagnostaras, S. G., Josselyn, S. A., Frankland, P. W. & Silva, A. J. Computer-assisted behavioral assessment of Pavlovian fear conditioning in mice. Learn. Mem. 7, 58–72 (2000).
Bourtchouladze, R. et al. Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learn. Mem. 5, 365–374 (1998).
Bontempi, B., Laurent-Demir, C., Destrade, C. & Jaffard, R. Time-dependent reorganization of brain circuitry underlying long-term memory storage. Nature 400, 671–675 (1999).
Shimizu, E., Tang, Y. P., Rampon, C. & Tsien, J. Z. NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 290, 1170–1174 (2000).
Morris, R. G. M., Garrud, P., Rawlins, J. N. P. & O'Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982).
Mumby, D. G., Astur, R. S., Weisend, M. P. & Sutherland, R. J. Retrograde amnesia and selective damage to the hippocampal formation: memory for places and object discriminations. Behav. Brain Res. 106, 97–107 (1999).
Riedel, G. et al. Reversible neural inactivation reveals hippocampal participation in several memory processes. Nature Neurosci. 2, 898–905 (1998).
Knowlton, B. J. & Fanselow, M. S. The hippocampus, consolidation and on-line memory. Curr. Opin. Neurobiol. 8, 293–296 (1998).
Whishaw, I. Q., McKenna, J. E. & Maaswinkel, H. Hippocampal lesions and path integration. Curr. Opin. Neurobiol. 7, 228–234 (1997).
Kirkwood, A., Silva, A. & Bear, M. F. Age-dependent decrease of synaptic plasticity in the neocortex of alphaCaMKII mutant mice. Proc. Natl Acad. Sci. USA 94, 3380–3383 (1997).
Scoville, W. B. & Milner, B. Loss of recent memory after hippocampal bilateral lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–12 (1957).
Rempel-Clower, N. L., Zola, S. M., Squire, L. R. & Amaral, D. G. Three cases of enduring memory impairment after bilateral damage limited to the hippocampal formation. J. Neurosci. 16, 5233–5255 (1996).
Zola-Morgan, S. M. & Squire, L. R. The primate hippocampal formation: evidence for a time-limited role in memory storage. Science 250, 288–290 (1990).
Nadel, L. & Moscovitch, M. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr. Opin. Neurobiol. 7, 217–227 (1997).
Cho, Y. H., Beracochea, D. & Jaffard, R. Extended temporal gradient for the retrograde and anterograde amnesia produced by ibotenate entorhinal cortex lesions in mice. J. Neurosci. 13, 1759–1766 (1993).
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).
Glazewski, S., Giese, K., Silva, A. & Fox, K. The role of alpha-CaMKII autophosphorylation in neocortical experience-dependent plasticity. Nature Neurosci. 3, 911–918 (2000).
Bourtchuladze, R. et al. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79, 59–68 (1994).
Kirkwood, A. & Bear, M. F. Hebbian synapses in visual cortex. J. Neurosci. 14, 1634–1645 (1994).
Acknowledgements
We thank S. Anagnostaras, R. Costa, S. Josselyn, S. Köhler, S. Kushner, G. Murphy and K. Nader for comments on the paper. These studies were supported by grants from NIH, National Eye Institute (A.K.), FRAXA Research Foundation (P.W.F.), and the Whitehall, Beckman, Merck, Klingenstein and McKnight Foundations (A.J.S.).
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Frankland, P., O'Brien, C., Ohno, M. et al. α-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature 411, 309–313 (2001). https://doi.org/10.1038/35077089
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DOI: https://doi.org/10.1038/35077089
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