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Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system

Nature Neuroscience volume 6, pages 231–242 (2003)Cite this article

A Corrigendum to this article was published on 01 March 2006

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.

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Figure 1: Synaptic activity bidirectionally and reversibly regulates the composition of the PSD.
Figure 2: Postsynaptic protein ensembles coregulated by activity.
Figure 3: Activity-dependent accumulation or reduction of PSD proteins at synaptic sites.
Figure 4: Activity level controls protein half-life in synaptic fractions.
Figure 5: Synaptic activity increases ubiquitin conjugation of PSD proteins.
Figure 6: Activity regulates ubiquitination of the postsynaptic scaffolds Shank, GKAP and AKAP79/150.
Figure 7: Activity-dependent remodeling of the PSD results from ubiquitin-proteasome–mediated degradation.
Figure 8: Activity level and proteasome-mediated degradation regulate synaptic signaling.

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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.

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  1. Department of Neurobiology, Box 3209, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Michael D. Ehlers

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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

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