Pentraxin 3 regulates synaptic function by inducing AMPA receptor clustering via ECM remodeling and β1-integrin

Giuliana Fossati, Davide Pozzi, Alice Canzi, Filippo Mirabella, Sonia Valentino, Raffaella Morini, Elsa Ghirardini, Fabia Filipello, Milena Moretti, Cecilia Gotti, Douglas S. Annis, Deane F. Mosher, Cecilia Garlanda, Barbara Bottazzi, Giulia Taraboletti, Alberto Mantovani, Michela Matteoli, Elisabetta Menna

Research output: Contribution to journalArticlepeer-review

Abstract

Control of synapse number and function in the developing central nervous system is critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors that promote the formation of excitatory synapses. Astrocyte-secreted thrombospondins (TSPs) induce the formation of structural synapses, which however remain post-synaptically silent, suggesting that completion of early synaptogenesis may require a two-step mechanism. Here, we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain. PTX3 plays a key role in promoting functionally-active CNS synapses, by increasing the surface levels and synaptic clustering of AMPA glutamate receptors. This process involves tumor necrosis factor-induced protein 6 (TSG6), remodeling of the perineuronal network, and a β1-integrin/ERK pathway. Furthermore, PTX3 activity is regulated by TSP1, which directly interacts with the N-terminal region of PTX3. These data unveil a fundamental role of PTX3 in promoting the first wave of synaptogenesis, and show that interplay of TSP1 and PTX3 sets the proper balance between synaptic growth and synapse function in the developing brain.

Original languageEnglish
Article numbere99529
JournalEMBO Journal
Volume38
Issue number1
DOIs
Publication statusPublished - Jan 3 2019

Keywords

  • AMPARs
  • astrocyte
  • PTX3
  • synapse
  • thrombospondin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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