Abstract
Bidirectional changes in the efficacy of neuronal synaptic transmission, such as hippocampal long-term potentiation (LTP) and long-term depression (LTD), are thought to be mechanisms for information storage in the brain1,2,3,4. LTP and LTD may be mediated by the modulation of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazloe proprionic acid) receptor phosphorylation5,6,7. Here we show that LTP and LTD reversibly modify the phosphorylation of the AMPA receptor GluR1 subunit. However, contrary to the hypothesis that LTP and LTD are the functional inverse of each other, we find that they are associated with phosphorylation and dephosphorylation, respectively, of distinct GluR1 phosphorylation sites. Moreover, the site modulated depends on the stimulation history of the synapse. LTD induction in naive synapses dephosphorylates the major cyclic-AMP-dependent protein kinase (PKA) site, whereas in potentiated synapses the major calcium/calmodulin-dependent protein kinase II (CaMKII) site is dephosphorylated. Conversely, LTP induction in naive synapses and depressed synapses increases phosphorylation of the CaMKII site and the PKA site, respectively. LTP is differentially sensitive to CaMKII and PKA inhibitors depending on the history of the synapse. These results indicate that AMPA receptor phosphorylation is critical for synaptic plasticity, and that identical stimulation conditions recruit different signal-transduction pathways depending on synaptic history.
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References
Bliss, T. V. P. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 ( 1993).
Bear, M. F. & Abraham, W. C. Long-term depression in hippocampus. Annu. Rev. Neurosci. 19, 437– 462 (1996).
Bear, M. F. A synaptic basis for memory storage in the cerebral cortex. Proc. Natl Acad. Sci. USA 93, 13453–13459 (1996).
Malenka, R. C. & Nicoll, R. A. Long-term potentiation—a decade of progress? Science 285, 1870– 1874 (1999).
Barria, A., Muller, D., Derkach, V., Griffith, L. C. & Soderling, T. R. Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation. Science 276, 2042–2045 (1997).
Lee, H. -K., Kameyama, K., Huganir, R. L. & Bear, M. F. NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21 , 1151–1162 (1998).
Kameyama, K., Lee, H. -K., Bear, M. F. & Huganir, R. L. Involvement of a postsynaptic protein kinase A substrate in the expression of homosynaptic long-term depression. Neuron 21, 1163– 1175 (1998).
Hollmann, M. & Heinemann, S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994).
Seeburg, P. H. The molecular biology of mammalian glutamate receptor channels. Trends Neurosci. 16, 359–365 (1993).
Squire, L. R. Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195– 231 (1992).
Zamanillo, D. et al. Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284, 1805–1811 (1999).
Roche, K. W., O'Brien, R. J., Mammen, A. L., Bernhardt, J. & Huganir, R. L. Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 16, 1179–1188 ( 1996).
Barria, A., Derkach, V. & Soderling, T. Identification of the Ca2+/calmodulin-dependent protein kinase II regulatory phosphorylation site in the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate type glutamate receptor. J. Biol. Chem. 272, 32727–32730 (1997).
Mammen, A. L., Kameyame, K., Roche, K. W. & Huganir, R. L. Phosphorylation of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II. J. Biol. Chem. 272, 32528–32533 (1997).
Derkach, V., Barria, A. & Soderling, T. R. Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc. Natl Acad. Sci. USA 96, 3269–3274 (1999).
Banke, T. B. et al. Control of GLuR1 AMPA receptor function by cAMP-dependent protein kinase. J. Neurosci. 20, 89 –102 (2000).
Mulkey, R. M., Herron, C. E. & Malenka, R. C. An essential role for protein phosphatases in hippocampal long-term depression. Science 261, 1051– 1055 (1993).
Mulkey, R. M., Endo, S., Shenolikar, S. & Malenka, R. C. Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369, 486– 488 (1994).
Malenka, R. C. et al. Long-term potentiation: an essential role for postsynaptic calmodulin and protein kinase activity. Nature 340, 554–557 (1989).
Malinow, R., Schulman, H. & Tsien, R. W. Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science 245, 862–866 (1989).
Lledo, P.-M. et al. Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism. Proc. Natl Acad. Sci. USA 92, 11175–11179 (1995).
Otmakhov, N., Griffith, L. C. & Lisman, J. E. Postsynaptic inhibitors of calcium/calmodulin-dependent protein kinase type II block induction but not maintenance of pairing-induced long-term potentiation. J. Neurosci. 17, 5357–5365 (1997).
Abeliovich, A. et al. Modified hippocampal long-term potentiation in PKC gamma-mutant mice. Cell 75, 1253–1262 (1993).
Benke, T. A., Luthi, A., Isaac, J. T. & Collingridge, G. L. Modulation of AMPA receptor unitary conductance by synaptic activity. Nature 393, 793–797 ( 1998).
Carroll, R. C., Lissing, D. V., von Zastrow, M., Nicoll, R. A. & Malenka, R. C. Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures. Nature Neurosci. 2, 454–460 (1999).
Shi, S. H. et al. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284 , 1811–1816 (1999).
Dudek, S. M. & Bear, M. F. Homosynaptic long-term depression in area CA1 of hippocampus and the effects of NMDA receptor blockade. Proc. Natl Acad. Sci. USA 89, 4363– 4367 (1992).
Acknowledgements
We thank C. Doherty for help in preparing the antibodies and D. Bury for help with the manuscript. This work was supported by the Howard Hughes Medical Institute, NARSAD and The Grable Foundation.
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Lee, HK., Barbarosie, M., Kameyama, K. et al. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000). https://doi.org/10.1038/35016089
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DOI: https://doi.org/10.1038/35016089
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