Abstract
Experience-dependent remodeling of the postsynaptic density (PSD) is critical for synapse formation and plasticity in the mammalian brain. Here, in cultured rat hippocampal neurons, I found long-lasting, global changes in the molecular composition of the PSD dictated by synaptic activity. These changes were bidirectional, reversible, modular, and involved multiple classes of PSD proteins. Moreover, activity-dependent remodeling was accompanied by altered protein turnover, occurred with corresponding increases or decreases in ubiquitin conjugation of synaptic proteins and required proteasome-mediated degradation. These modifications, in turn, reciprocally altered synaptic signaling to the downstream effectors CREB (cyclic AMP response element binding protein) and ERK-MAPK (extracellular signal regulated kinase–MAP kinase). These results indicate that activity regulates postsynaptic composition and signaling through the ubiquitin-proteasome system, providing a mechanistic link between synaptic activity, protein turnover and the functional reorganization of synapses.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Yuste, R. & Bonhoeffer, T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu. Rev. Neurosci. 24, 1071–1089 (2001).
Luscher, C., Nicoll, R.A., Malenka, R.C. & Muller, D. Synaptic plasticity and dynamic modulation of the postsynaptic membrane. Nat. Neurosci. 3, 545–550 (2000).
Husi, H., Ward, M.A., Choudhary, J.S., Blackstock, W.P. & Grant, S.G. Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat. Neurosci. 3, 661–669 (2000).
Sheng, M. & Kim, M.J. Postsynaptic signaling and plasticity mechanisms. Science 298, 776–780 (2002).
Murthy, V.N., Schikorski, T., Stevens, C.F. & Zhu, Y. Inactivity produces increases in neurotransmitter release and synapse size. Neuron 32, 673–682 (2001).
Geinisman, Y., deToledo-Morrell, L. & Morrell, F. Induction of long-term potentiation is associated with an increase in the number of axospinous synapses with segmented postsynaptic densities. Brain Res. 566, 77–88 (1991).
Toni, N., Buchs, P.A., Nikonenko, I., Bron, C.R. & Muller, D. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402, 421–425 (1999).
Okabe, S., Kim, H.D., Miwa, A., Kuriu, T. & Okado, H. Continual remodeling of postsynaptic density and its regulation by synaptic activity. Nat. Neurosci. 2, 804–811 (1999).
Marrs, G.S., Green, S.H. & Dailey, M.E. Rapid formation and remodeling of postsynaptic densities in developing dendrites. Nat. Neurosci. 4, 1006–1013 (2001).
Meyer, T. & Shen, K. In and out of the postsynaptic region: signaling proteins on the move. Trends Cell Biol. 10, 238–244 (2000).
Turrigiano, G.G. & Nelson, S.B. Hebb and homeostasis in neuronal plasticity. Curr. Opin. Neurobiol. 10, 358–364 (2000).
Rao, A. & Craig, A.M. Activity regulates the synaptic localization of the NMDA receptor in hippocampal neurons. Neuron 19, 801–812 (1997).
O'Brien, R.J. et al. Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron 21, 1067–1078 (1998).
Malinow, R. & Malenka, R.C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).
Thiagarajan, T.C., Piedras-Renteria, E.S. & Tsien, R.W. alpha- and beta-CaMKII: inverse regulation by neuronal activity and opposing effects on synaptic strength. Neuron 36, 1103–1114 (2002).
West, A.E. et al. Calcium regulation of neuronal gene expression. Proc. Natl. Acad. Sci. USA 98, 11024–11031 (2001).
Steward, O. & Schuman, E.M. Protein synthesis at synaptic sites on dendrites. Annu. Rev. Neurosci. 24, 299–325 (2001).
Adams, J.P. & Sweatt, J.D. Molecular psychology: roles for the ERK MAP kinase cascade in memory. Annu. Rev. Pharmacol. Toxicol. 42, 135–163 (2002).
Glickman, M.H. & Ciechanover, A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol. Rev. 82, 373–428 (2002).
Hicke, L. Protein regulation by monoubiquitin. Nat. Rev. Mol. Cell. Biol. 2, 195–201 (2001).
Hegde, A.N. et al. Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. Cell 89, 115–126 (1997).
Jiang, Y.H. et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21, 799–811 (1998).
DiAntonio, A. et al. Ubiquitination-dependent mechanisms regulate synaptic growth and function. Nature 412, 449–452 (2001).
Wilson, S.M. et al. Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Nat. Genet. 7, 7 (2002).
Murphey, R. & Godenschwege, T. New roles for ubiquitin in the assembly and function of neuronal circuits. Neuron 36, 5 (2002).
Hegde, A.N. & DiAntonio, A. Ubiquitin and the synapse. Nat. Rev. Neurosci. 3, 854–861 (2002).
Burbea, M., Dreier, L., Dittman, J.S., Grunwald, M.E. & Kaplan, J.M. Ubiquitin and AP180 regulate the abundance of GLR-1 glutamate receptors at postsynaptic elements in C. elegans. Neuron 35, 107–120 (2002).
Chapman, A.P., Smith, S.J., Rider, C.C. & Beesley, P.W. Multiple ubiquitin conjugates are present in rat brain synaptic membranes and postsynaptic densities. Neurosci. Lett. 168, 238–242 (1994).
Cho, K.O., Hunt, C.A. & Kennedy, M.B. The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs—large tumor suppressor protein. Neuron 9, 929–942 (1992).
Watt, A.J., van Rossum, M.C., MacLeod, K.M., Nelson, S.B. & Turrigiano, G.G. Activity co-regulates quantal AMPA and NMDA currents at neocortical synapses. Neuron 26, 659–670 (2000).
Ehlers, M.D. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28, 511–525 (2000).
Boeckers, T.M., Bockmann, J., Kreutz, M.R. & Gundelfinger, E.D. ProSAP/Shank proteins—a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease. J. Neurochem. 81, 903–910 (2002).
Liao, D., Zhang, X., O'Brien, R., Ehlers, M.D. & Huganir, R.L. Regulation of morphological postsynaptic silent synapses in developing hippocampal neurons. Nat. Neurosci. 2, 37–43 (1999).
Turrigiano, G.G., Leslie, K.R., Desai, N.S., Rutherford, L.C. & Nelson, S.B. Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391, 892–896 (1998).
Deveraux, Q., Ustrell, V., Pickart, C. & Rechsteiner, M. A 26 S protease subunit that binds ubiquitin conjugates. J. Biol. Chem. 269, 7059–7061 (1994).
Michel, J.J. & Scott, J.D. AKAP mediated signal transduction. Annu. Rev. Pharmacol. Toxicol. 42, 235–257 (2002).
Lonze, B.E. & Ginty, D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605–623 (2002).
Lu, W. et al. Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243–254 (2001).
Hardingham, G.E., Arnold, F.J. & Bading, H. A calcium microdomain near NMDA receptors: on switch for ERK-dependent synapse-to-nucleus communication. Nat. Neurosci. 4, 565–566 (2001).
Hardingham, G.E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414 (2002).
Tovar, K.R. & Westbrook, G.L. Mobile NMDA receptors at hippocampal synapses. Neuron 34, 255–264 (2002).
Sala, C., Rudolph-Correia, S. & Sheng, M. Developmentally regulated NMDA receptor-dependent dephosphorylation of cAMP response element-binding protein (CREB) in hippocampal neurons. J. Neurosci. 20, 3529–3536 (2000).
Akaaboune, M., Culican, S.M., Turney, S.G. & Lichtman, J.W. Rapid and reversible effects of activity on acetylcholine receptor density at the neuromuscular junction in vivo. Science 286, 503–507 (1999).
Chain, D.G. et al. Mechanisms for generating the autonomous cAMP-dependent protein kinase required for long-term facilitation in Aplysia. Neuron 22, 147–156 (1999).
Campbell, D.S. & Holt, C.E. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32, 1013–1026 (2001).
Luscher, C. et al. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24, 649–658 (1999).
Fong, D.K., Rao, A., Crump, F.T. & Craig, A.M. Rapid synaptic remodeling by protein kinase C: reciprocal translocation of NMDA receptors and calcium/calmodulin-dependent kinase II. J. Neurosci. 22, 2153–2164 (2002).
Minichiello, L. et al. Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 36, 121 (2002).
Wu, G.Y., Deisseroth, K. & Tsien, R.W. Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology. Nat. Neurosci. 4, 151–158 (2001).
Mammen, A.L., Huganir, R.L. & O'Brien, R.J. Redistribution and stabilization of cell surface glutamate receptors during synapse formation. J. Neurosci. 17, 7351–7358 (1997).
Acknowledgements
I thank C. Zhang for technical help and J. Hernandez, G. Augustine, T. Blanpied, G. Feng, D. Fitzpatrick, A. Horton, L. Katz, J. McNamara, R. Mooney, Y. Mu, I. Perez-Otano, D. Scott and P. Skene for comments and advice. This work was supported by grants from the NIH (NS39402 and MH64748), McKnight Foundation, Klingenstein Fund, Spinal Cord Research Foundation, NARSAD, Sloan Foundation, Ellison Foundation, Alzheimer's Association and the Muscular Dystrophy Association.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Ehlers, M. Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci 6, 231–242 (2003). https://doi.org/10.1038/nn1013
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn1013
This article is cited by
-
Post-ischemic ubiquitination at the postsynaptic density reversibly influences the activity of ischemia-relevant kinases
Communications Biology (2024)
-
Synaptic proteasome is inhibited in Alzheimer’s disease models and associates with memory impairment in mice
Communications Biology (2023)
-
Functional network disorganization and cognitive decline following fractionated whole-brain radiation in mice
GeroScience (2023)
-
USP39 is essential for mammalian epithelial morphogenesis through upregulation of planar cell polarity components
Communications Biology (2022)
-
DNA methylation signatures in human neonatal blood following maternal antenatal corticosteroid treatment
Translational Psychiatry (2022)