Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors
Open accessAbstract
In the developing central nervous system (CNS), the control of synapse number and function is critical to the formation of neural circuits. We previously demonstrated that astrocyte-secreted factors powerfully induce the formation of functional excitatory synapses between CNS neurons. Astrocyte-secreted thrombospondins induce the formation of structural synapses, but these synapses are postsynaptically silent. Here we use biochemical fractionation of astrocyte-conditioned medium to identify glypican 4 (Gpc4) and glypican 6 (Gpc6) as astrocyte-secreted signals sufficient to induce functional synapses between purified retinal ganglion cell neurons, and show that depletion of these molecules from astrocyte-conditioned medium significantly reduces its ability to induce postsynaptic activity. Application of Gpc4 to purified neurons is sufficient to increase the frequency and amplitude of glutamatergic synaptic events. This is achieved by increasing the surface level and clustering, but not overall cellular protein level, of the GluA1 subunit of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamate receptor (AMPAR). Gpc4 and Gpc6 are expressed by astrocytes in vivo in the developing CNS, with Gpc4 expression enriched in the hippocampus and Gpc6 enriched in the cerebellum. Finally, we demonstrate that Gpc4-deficient mice have defective synapse formation, with decreased amplitude of excitatory synaptic currents in the developing hippocampus and reduced recruitment of AMPARs to synapses. These data identify glypicans as a family of novel astrocyte-derived molecules that are necessary and sufficient to promote glutamate receptor clustering and receptivity and to induce the formation of postsynaptically functioning CNS synapses.
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Astrocytes regulate synapse number by secreting synaptogenic signals such as thrombospondins, hevin, and glypicans that induce synapse formation.
“In the developing brain, astrocytes regulate synapse number by secreting synaptogenic signals, such as thrombospondins, hevin, and glypicans, that induce synapse formation (Allen et al., 2012; Christopherson et al., 2005; Kucukdereli et al., 2011)”
From The aging astrocyte transcriptome from multiple regions of the mouse brain. (2018) · cites this paper as Allen et al., 2012
Gpc4 and Gpc6 are astrocytic factors that stimulate excitatory synapse formation by regulating glutamate receptor clustering.
“In line with this, Gpc4 and Gpc6 were recently also discovered as astrocytic factors, which stimulate the excitatory synapse formation by regulating glutamate receptor clustering57.”
From Elimination of the four extracellular matrix molecules tenascin-C, tenascin-R, brevican and neurocan alters the ratio of excitatory and inhibitory synapses (2019) · cites this paper as [57]
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- Authors
- Allen, N. J., Bennett, M. L., Foo, L. C., Wang, G. X., Chakraborty, C., Smith, S. J., & Barres, B. A.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Allen, Nicola J.
- ORCID
- Venue
- Nature
- Published
- 2012-05-27
- Volume
- 486
- Issue
- 7403
- Pages
- 410-414
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3383085
- OpenAlex
- W2012935976
- Cited by
- 764
- References
- 32
- Citations by year
- 2026: 49 · 2025: 58 · 2024: 61 · 2023: 72 · 2022: 61 · 2021: 72 · 2020: 64 · 2019: 47 · 2018: 43 · 2017: 56 · 2016: 39 · 2015: 48 · 2014: 46 · 2013: 36 · 2012: 11
- FWCI
- 18.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Drug Abuse (R01DA015043)
- National Institute of Neurological Disorders and Stroke (R01NS0725252, R01NS075252, R01NS077601)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- GPC4, astrocytes, excitatory synapse formation, retinal ganglion cells, glutamatergic neurotransmission, synaptic plasticity, synaptic dysfunction, astrocyte-neuron interaction, hippocampus
- MeSH terms
- Animals, Astrocytes, Cerebellum, Female, Hippocampus, Humans, Male, Mice, Inbred C57BL, Retinal Ganglion Cells, Synapses, Culture Media, Conditioned, Rats, Sprague-Dawley, Receptors, AMPA, Excitatory Postsynaptic Potentials, Mice, Rats, Glypicans
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