Astrocyte-Secreted Glypican 4 Regulates Release of Neuronal Pentraxin 1 from Axons to Induce Functional Synapse Formation

Neuron. 2017 Oct 11;96(2):428-445.e13. doi: 10.1016/j.neuron.2017.09.053.


The generation of precise synaptic connections between developing neurons is critical to the formation of functional neural circuits. Astrocyte-secreted glypican 4 induces formation of active excitatory synapses by recruiting AMPA glutamate receptors to the postsynaptic cell surface. We now identify the molecular mechanism of how glypican 4 exerts its effect. Glypican 4 induces release of the AMPA receptor clustering factor neuronal pentraxin 1 from presynaptic terminals by signaling through presynaptic protein tyrosine phosphatase receptor δ. Pentraxin then accumulates AMPA receptors on the postsynaptic terminal forming functional synapses. Our findings reveal a signaling pathway that regulates synaptic activity during central nervous system development and demonstrates a role for astrocytes as organizers of active synaptic connections by coordinating both pre and post synaptic neurons. As mutations in glypicans are associated with neurological disorders, such as autism and schizophrenia, this signaling cascade offers new avenues to modulate synaptic function in disease.

Keywords: AMPAR; astrocyte; development; glia; glypican; neuronal pentraxin 1; synapse.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Astrocytes / metabolism*
  • Axons / metabolism*
  • C-Reactive Protein / genetics
  • C-Reactive Protein / metabolism*
  • Cells, Cultured
  • Female
  • Glypicans
  • HEK293 Cells
  • Heparan Sulfate Proteoglycans / metabolism*
  • Heparan Sulfate Proteoglycans / physiology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism
  • Retinal Ganglion Cells / metabolism
  • Synapses / genetics
  • Synapses / metabolism*


  • Glypicans
  • Gpc4 protein, mouse
  • Heparan Sulfate Proteoglycans
  • Nerve Tissue Proteins
  • Receptors, AMPA
  • neuronal pentraxin
  • C-Reactive Protein