Research ResourceNeuroscience

Long-term potentiation modulates synaptic phosphorylation networks and reshapes the structure of the postsynaptic interactome

Sci. Signal.  09 Aug 2016:
Vol. 9, Issue 440, pp. rs8
DOI: 10.1126/scisignal.aaf6716

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Defining the PSD risk for psychiatric disease

Li et al. stimulated mouse hippocampi to induce long-term potentiation (LTP; a form of synaptic plasticity), isolated the CA1 region, and then performed both a proteomic analysis and a protein-protein interaction analysis of the postsynaptic density (PSD), a cellular compartment containing more than 1500 proteins. Bioinformatics analysis of this data set indicated that risk factors associated with autism spectrum disorder and schizophrenia were contained within the phosphoproteins that were differentially regulated by the induction of LTP, such that excluding these proteins from the analysis completely removed any association with the risk of having either of these two psychiatric diseases. The data provided, along with this medical association of disease risk, should guide researchers and clinicians toward a better understanding of both the molecular changes that enable learning and memory as well as the complex neurological diseases involving proteins that are part of the PSD.

Abstract

The postsynaptic site of neurons is composed of more than 1500 proteins arranged in protein-protein interaction complexes, the composition of which is modulated by protein phosphorylation through the actions of complex signaling networks. Components of these networks function as key regulators of synaptic plasticity, in particular hippocampal long-term potentiation (LTP). The postsynaptic density (PSD) is a complex multicomponent structure that includes receptors, enzymes, scaffold proteins, and structural proteins. We triggered LTP in the mouse hippocampus CA1 region and then performed large-scale analyses to identify phosphorylation-mediated events in the PSD and changes in the protein-protein interactome of the PSD that were associated with LTP induction. Our data indicated LTP-induced reorganization of the PSD. The dynamic reorganization of the PSD links glutamate receptor signaling to kinases (writers) and phosphatases (erasers), as well as the target proteins that are modulated by protein phosphorylation and the proteins that recognize the phosphorylation status of their binding partners (readers). Protein phosphorylation and protein interaction networks converged at highly connected nodes within the PSD network. Furthermore, the LTP-regulated phosphoproteins, which included the scaffold proteins Shank3, Syngap1, Dlgap1, and Dlg4, represented the “PSD risk” for schizophrenia and autism spectrum disorder, such that without these proteins in the analysis, the association with the PSD and these two psychiatric diseases was not present. These data are a rich resource for future studies of LTP and suggest that the PSD holds the keys to understanding the molecular events that contribute to complex neurological disorders that affect synaptic plasticity.

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