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

• Published in: Neuron (Cambridge, Mass.) Vol. 96; no. 2; pp. 428 - 445.e13
• Main Authors: Farhy-Tselnicker, Isabella, van Casteren, Adriana C.M., Lee, Aletheia, Chang, Veronica T., Aricescu, A. Radu, Allen, Nicola J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-10-2017; Elsevier Limited; Cell Press
• Subjects: Amino Acid Sequence; AMPAR; Animals; astrocyte; Astrocytes; Astrocytes - metabolism; Autism; Axons; Axons - metabolism; C-Reactive Protein - genetics; C-Reactive Protein - metabolism; Cell surface; Cells, Cultured; Central nervous system; development; Female; Functional morphology; Gene expression; glia; Glutamic acid receptors; glypican; Glypicans; HEK293 Cells; Heparan sulfate proteoglycans; Heparan Sulfate Proteoglycans - metabolism; Heparan Sulfate Proteoglycans - physiology; Humans; Kinases; Male; Mental disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural networks; Neurological diseases; neuronal pentraxin 1; Neurons; Pentraxins; Phosphatase; Protein-tyrosine-phosphatase; Proteins; Rats; Rats, Sprague-Dawley; Receptor density; Receptors, AMPA - metabolism; Retinal Ganglion Cells - metabolism; Schizophrenia; Signal transduction; synapse; Synapses; Synapses - genetics; Synapses - metabolism; Synaptogenesis; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; development; neuronal pentraxin 1; synapse; glypican; astrocyte; glia; AMPAR
• ISSN: 0896-6273; 1097-4199
• 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.
•Astrocyte-secreted Gpc4 induces release of NP1 from neurons•Release of NP1 is mediated through Gpc4 interaction with presynaptic RPTPδ•Gpc4 or RPTPδ KO causes presynaptic NP1 retention and decreased synapse number•Astrocytic release of Gpc4 provides spatial and temporal cues for synaptogenesis
Astrocytes are important regulators of synapse formation. Farhy-Tselnicker et al. identify the molecular pathway of active neuronal synapse formation induced by astrocyte-secreted glypican 4. These data functionally link astrocytes to signaling cascades activated in both pre- and postsynaptic neurons.