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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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A Kinase Anchor Proteins
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Adaptor Proteins, Signal Transducing*
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Animals
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Carrier Proteins / analysis
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Carrier Proteins / metabolism
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cysteine Endopeptidases / metabolism*
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Hippocampus / cytology
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Mitogen-Activated Protein Kinases / metabolism
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Multienzyme Complexes / metabolism*
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Nerve Tissue Proteins / analysis
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Nerve Tissue Proteins / metabolism
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Proteasome Endopeptidase Complex
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Rats
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Receptors, N-Methyl-D-Aspartate / metabolism
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Signal Transduction / physiology*
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Synapses / chemistry
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Synapses / metabolism*
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Synaptic Transmission / physiology*
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Ubiquitin / metabolism*
Substances
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A Kinase Anchor Proteins
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Adaptor Proteins, Signal Transducing
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Akap5 protein, rat
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Carrier Proteins
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Cyclic AMP Response Element-Binding Protein
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Multienzyme Complexes
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Nerve Tissue Proteins
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Receptors, N-Methyl-D-Aspartate
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Ubiquitin
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postsynaptic density proteins
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Mitogen-Activated Protein Kinases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex