Journal
NEURON
Volume 96, Issue 2, Pages 428-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2017.09.053
Keywords
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Funding
- NIH-NINDS [R01 NS089791]
- Hearst Foundation
- Pew Foundation
- Ellison Foundation
- Dana Foundation
- Whitehall Foundation
- Larry and Carol Greenfield
- Catarina Foundation
- Wellcome Trust
- UK Medical Research Council (MRC) [L009609, MC_UP_1201/15]
- Core Facilities of the Salk Institute [NIH-NCI CCSG P30 014195, NIH-NINDS P30 NS072031]
- Wellcome Trust Centre for Human Genetics [090532/Z/09/Z]
- Medical Research Council [MC_UP_1201/15, MR/L009609/1] Funding Source: researchfish
- MRC [MC_UP_1201/15, MR/L009609/1] Funding Source: UKRI
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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 delta. 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.
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