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Cited by 15Extracellular vesicles in diseaseCellular transport and secretionNeuroscience and Neuropharmacology Research

An independent regulator of global release pathways in astrocytes generates a subtype of extracellular vesicles required for postsynaptic function

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Levy-Myers, Reuben, Daudelin, Daniel, Na, Chan Hyun, Sockanathan, Shanthini·2023·Science Advances
DOI 10.1126/sciadv.adg2067PMC PMC10289663
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Abstract

Extracellular vesicles (EVs) are heterogeneous in size, composition, and function. We show that the six-transmembrane protein glycerophosphodiester phosphodiesterase 3 (GDE3) regulates actin remodeling, a global EV biogenic pathway, to release an EV subtype with distinct functions. GDE3 is necessary and sufficient for releasing EVs containing annexin A1 and GDE3 from the plasma membrane via Wiskott-Aldrich syndrome protein family member 3 (WAVE3), a major regulator of actin dynamics. GDE3 is expressed in astrocytes but not neurons, yet mice lacking GDE3 [ Gde3 knockout (KO)] have decreased miniature excitatory postsynaptic current (mEPSC) amplitudes in hippocampal CA1 neurons. EVs from cultured wild-type astrocytes restore mEPSC amplitudes in Gde3 KOs, while EVs from Gde3 KO astrocytes or astrocytes inhibited for WAVE3 actin branching activity do not. Thus, GDE3-WAVE3 is a nonredundant astrocytic pathway that remodels actin to release a functionally distinct EV subtype, supporting the concept that independent regulation of global EV release pathways differentially regulates EV signaling within the cellular EV landscape.

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  • WAVE3 is expressed mainly in the brain, where its levels in interneurons and astrocytes are relatively high.

    “WAVE3 is also expressed mainly in the brain16, where its levels in interneurons and astrocytes are relatively high17,18.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [17]

    The Results section ('GDE3 promotes MV release by regulating WAVE3-dependent actin remodeling'; page unavailable) says WAVE3 is enriched in astrocytes and demonstrates its expression in cultured astrocytes. It does not establish relatively high WAVE3 levels in interneurons. The separate citation attached to 'mainly in the brain' is not assessed here. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Levy-Myers, R., Daudelin, D., Na, C. H., & Sockanathan, S.
Affiliations
Johns Hopkins University (US)
Corresponding author
Sockanathan, Shanthini
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2023-06-23
Volume
9
Issue
25
Pages
eadg2067-eadg2067
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.adg2067
PMC
PMC10289663
OpenAlex
W4381804053
Cited by
15
References
8
Citations by year
2026: 1 · 2025: 6 · 2024: 6 · 2023: 2
FWCI
1.33
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (1s10od021844-01)
  • National Institute on Aging (R56AG056169, F31AG067632, R01AG056169, U19AG065169)
  • National Institute of General Medical Sciences (T32GM007445)
  • National Institute of Neurological Disorders and Stroke (R01NS046336, T32NS091018)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
extracellular vesicles, GDE3, WAVE3, astrocytes, actin cytoskeleton remodeling, actin filament branching, annexin A1, miniature excitatory postsynaptic currents, postsynaptic function, CA1 pyramidal neurons
MeSH terms
Extracellular Vesicles, Actins, Animals, Astrocytes, Cell Membrane, Signal Transduction, Mice

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