CPG15/Neuritin Mimics Experience in Selecting Excitatory Synapses for Stabilization by Facilitating PSD95 Recruitment

Cell Rep. 2019 Aug 6;28(6):1584-1595.e5. doi: 10.1016/j.celrep.2019.07.012.

Abstract

A key feature of brain plasticity is the experience-dependent selection of optimal connections, implemented by a set of activity-regulated genes that dynamically adjust synapse strength and number. The activity-regulated gene cpg15/neuritin has been previously implicated in stabilization and maturation of excitatory synapses. Here, we combine two-photon microscopy with genetic and sensory manipulations to dissect excitatory synapse formation in vivo and examine the role of activity and CPG15 in dendritic spine formation, PSD95 recruitment, and synapse stabilization. We find that neither visual experience nor CPG15 is required for spine formation. However, PSD95 recruitment to nascent spines and their subsequent stabilization requires both. Further, cell-autonomous CPG15 expression is sufficient to replace experience in facilitating PSD95 recruitment and spine stabilization. CPG15 directly interacts with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on immature dendritic spines, suggesting a signaling mode for this small extracellular molecule acting as an experience-dependent "selector" for spine stabilization and synapse maturation.

Keywords: AMPA receptors; CPG15; PSD95; activity-regulated genes; dendritic spines; excitatory synapses; in vivo two-photon microscopy; neuritin; visual experience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Dendritic Spines / metabolism*
  • Disks Large Homolog 4 Protein / metabolism*
  • Excitatory Postsynaptic Potentials
  • Female
  • GPI-Linked Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism*
  • Neuronal Plasticity
  • Receptors, AMPA / metabolism
  • Synapses / metabolism*

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • GPI-Linked Proteins
  • Nerve Tissue Proteins
  • Nrn1 protein, mouse
  • Receptors, AMPA