title: Long-term potentiation modulates synaptic phosphorylation networks and reshapes the structure of the postsynaptic interactome.
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.
authors: Zilkha Neurogenetic Institute, Los Angeles, CA, 90089, USA.
authors: Jing
authors: J
authors: Li
authors: Zilkha Neurogenetic Institute, Los Angeles, CA, 90089, USA.
authors: Brent
authors: B
authors: Wilkinson
authors: Zilkha Neurogenetic Institute, Los Angeles, CA, 90089, USA.
authors: Veronica A
authors: VA
authors: Clementel
authors: National Laboratory of Bio-Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors: Junjie
authors: J
authors: Hou
authors: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90024, USA.
authors: Thomas J
authors: TJ
authors: O'Dell
authors: Zilkha Neurogenetic Institute, Los Angeles, CA, 90089, USA. Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. coba@usc.edu.
authors: Marcelo P
authors: MP
authors: Coba
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology*; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
chemical_list: D010750:Phosphoproteins; D011494:Protein Kinases; D010749:Phosphoprotein Phosphatases