Pin1 modulates the synaptic content of NMDA receptors via prolyl-isomerization of PSD-95

Roberta Antonelli, Roberto de Filippo, Silvia Middei, Stefka Stancheva, Beatrice Pastore, Martine Ammassari-Teule, Andrea Barberis, Enrico Cherubini, Paola Zacchi

Research output: Contribution to journalArticle

Abstract

Phosphorylation of serine/threonine residues preceding a proline regulates the fate of its targets through postphosphorylation conformational changes catalyzed by the peptidyl-prolyl cis-/trans isomerase Pin1. By flipping the substrate between two different functional conformations, this enzyme exerts a fine-tuning of phosphorylation signals. Pin1 has been detected in dendritic spines and shafts where it regulates protein synthesis required to sustain the late phase of long-term potentiation (LTP). Here, we demonstrate that Pin1 residing in postsynaptic structures can interact with postsynaptic density protein-95 (PSD-95), a key scaffold protein that anchors NMDA receptors (NMDARs) in PSD via GluN2-type receptor subunits. Pin1 recruitment by PSD-95 occurs at specific serine-threonine/proline consensus motifs localized in the linker region connecting PDZ2 to PDZ3 domains. Upon binding, Pin1 triggers structural changes in PSD-95, thus negatively affecting its ability to interact with NMDARs. In electrophysiological experiments, larger NMDA-mediated synaptic currents, evoked in CA1 principal cells by Schaffer collateral stimulation, were detected in hippocampal slices obtained from Pin1−/− mice compared with controls. Similar results were obtained in cultured hippocampal cells expressing a PSD-95 mutant unable to undergo prolyl-isomerization, thus indicating that the action of Pin1 on PSD-95 is critical for this effect. In addition, an enhancement in spine density and size was detected in CA1 principal cells of Pin1−/− or in Thy-1GFP mice treated with the pharmacological inhibitor of Pin1 catalytic activity PiB. Our data indicate that Pin1 controls synaptic content of NMDARs via PSD-95 prolyl-isomerization and the expression of dendritic spines, both required for LTP maintenance.

Original languageEnglish
Pages (from-to)5437-5447
Number of pages11
JournalJournal of Neuroscience
Volume36
Issue number20
DOIs
Publication statusPublished - May 18 2016

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Keywords

  • Dendritic spines
  • Glutamatergic transmission
  • Hippocampus
  • NMDA receptors
  • Pin1
  • PSD-95

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Antonelli, R., de Filippo, R., Middei, S., Stancheva, S., Pastore, B., Ammassari-Teule, M., Barberis, A., Cherubini, E., & Zacchi, P. (2016). Pin1 modulates the synaptic content of NMDA receptors via prolyl-isomerization of PSD-95. Journal of Neuroscience, 36(20), 5437-5447. https://doi.org/10.1523/JNEUROSCI.3124-15.2016