Activity-dependent Protein Dynamics Define Interconnected Cores of Co-regulated Postsynaptic Proteins

University of California, United States
Molecular &amp Cellular Proteomics (Impact Factor: 6.56). 10/2012; 12(1). DOI: 10.1074/mcp.M112.019976
Source: PubMed


Synapses are highly dynamic structures that mediate cell-cell communication in the central nervous system. Their molecular composition is altered in an activity dependent fashion, which modulates the efficacy of subsequent synaptic transmission events. While activity-dependent trafficking of individual key synaptic proteins into and out of the synapse has been characterized previously, global activity-dependent changes in the synaptic proteome have not been studied. To test the feasibility of carrying out an unbiased large scale approach we investigated alterations in the molecular composition of synaptic spines following mass-stimulation of the central nervous system induced by pilocarpine. We observe widespread changes in relative synaptic abundances encompassing essentially all proteins, supporting the view that molecular composition of the PSD is tightly regulated. In most cases, we observe that members of gene families displayed coordinate regulation even when they were not known to physically interact. Analysis of correlated synaptic localization revealed a tightly co-regulated cluster of proteins, consisting of mainly glutamate receptors and their adaptors. This cluster constitutes a functional core of the postsynaptic machinery and changes in its amount impacts on synaptic strength and size. Our data show that the unbiased investigation of activity-dependent signaling of the PSD proteome can offer valuable new information on synaptic plasticity.

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Available from: Agnes Thalhammer, Nov 26, 2015
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    • "Here, we consider some recent studies that focused on protein fractions enriched for synaptic protein components. An interesting study by Trinidad et al. (2013) reported global activity-dependent changes in the murine synaptic proteome after massive activity onset utilizing the pilocarpine model of epilepsy. They followed the regulation of more than a 100 core protein components of the postsynaptic density that were defined based on previous studies (Sheng and Hoogenraad, 2007; Fernandez et al., 2009) during the first hour after pilocarpine application, assuming that this time window covers mainly the phase of redistribution between synapse-associated and cytoplasmic protein pools. "
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    • "We also applied hierarchical clustering, utilizing a Pearson’s correlation coefficient. Pearson’s has been shown to be a highly robust unsupervised correlation that performs well under a multitude of protein-protein interaction analyses, from identifying regulatory networks to identifying groups of proteins with shared functions [20,21]. A lack of a gold standard gene-disease-chemical network is also why no semi-supervised or supervised methods were chosen. "
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    • "These organized protein networks provide an efficient assembly for signal transduction and are regulated to allow strengthening and weakening of synaptic transmission. Moreover, protein constituents of the PSD are known to be dynamically influenced by synaptic activity, via mechanisms such as local translation, protein phosphorylation, ubiquitination, and degradation, as well as protein translocation into and out of synapses [9] [10]. "
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