Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors

By N. J. Allen, Mariko L. Bennett, L. Foo, Gordon X. Wang, C. Chakraborty, Stephen J. Smith, B. Barres. Nature, 2012

726 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/b1b96c85b196ea79acc373456b8fb73e54de6da6

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. M. Sofroniew
2. M. Pekny
3. M. Pekna
4. J. Burda
5. C. Eroglu
6. E. Hol
7. Alexei Verkhratsky
8. N. J. Allen

In Neurology

1. M. Sofroniew
2. M. Pekny
3. M. Pekna
4. J. Burda
5. E. Hol
6. Alexei Verkhratsky
7. C. Eroglu
8. N. J. Allen

In Physiology

1. M. Pekny
2. M. Pekna
3. B. Barres
4. J. Burda
5. S. A. Liddelow
6. Alexei Verkhratsky
7. E. Hol
8. Won-Suk Chung

Citations in the corpus

• Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and CNS inflammation via the aryl hydrocarbon receptor (2016, neutral): “pSOCS:AhR(1) forward, 5′CCAGCTCCCTACCTGTTTGA-3′, and reverse, 5′-GGAATGGAGCGGACAGGA-3′; pSOCS2:AhR(2) forward, 5′-ATGAGTCAACACGTCCCAGA-3′, and reverse, 5′CTGCACACTCTCGTTTTGGG-3′, pSOCS2:AhR(3), forward, 5′TGGCAAAGTCTCTCGCAGA-3′, and reverse, 5′-TGCTCGGGGTTAAATGGTAC-3′.”
• Reactive Astrocytes: Production, Function, and Therapeutic Potential. (2017, background): “As useful as these culture systems have been for the investigation of important astrocyte physiological functions (Christopherson et al., 2005; Eroglu et al., 2009; Allen et al., 2012), they are not representative of physiological astrocytes in vivo.”
• Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. (2015, background): “They are indispensable for proper brain development [5 ,6 ,7 ,8], play fundamental roles in maintaining ion, neurotransmitter, water [9] and energy homeostasis [10], and modulate neuronal signaling [11,12].”
• Astrocyte roles in traumatic brain injury (2015, background): “functionality (Allen et al., 2012).”
• The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain (2018, background): “(Allen et al., 2012; Christopherson et al., 2005; Kucukdereli et al., 2011) and by eliminating excess synapses by phagocytosis using the receptors Mertk and Megf10 and indirectly by inducing expression of complement cascade components in neurons (Bialas and Stevens, 2013; Chung et al.”
• Physiology of Astroglia. (2018, positive): “Astroglia-derived glypicans 4 and 6 facilitate synapse maturation by increasing the number of glutamatergic -amino-3-hydroxy-5-methyl-isoxazole propionate (AMPA) receptors at postsynaptic sites (24).”
• Astrocytes: a central element in neurological diseases (2016, background): “Astroglia-derived glypican-4 and 6 induce functional synapse maturation by increasing the number of AMPA receptors on synapses [5].”
• Astrocytes Control Synapse Formation, Function, and Elimination (2015, positive): “The finding that astrocyte-secreted factors are able to up-regulate the surface level of AMPARs on RGC neurons by threefold led to a biochemical study to identify the factor responsible (Allen et al. 2012).”
• Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse (2015, positive): “For example, purified neurons in culture have little ability to form functional synapses, which are powerfully promoted by astrocytes (Allen et al., 2012; Christopherson et al., 2005; Kucukdereli et al., 2011; Ullian et al., 2001).”