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Cited by 84Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model.

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Cheng, Connie, Lau, Sally K. M., Doering, Laurie C.·2016·Molecular Brain
DOI 10.1186/s13041-016-0256-9PMC PMC4971702
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Abstract

Astrocytes are key participants in various aspects of brain development and function, many of which are executed via secreted proteins. Defects in astrocyte signaling are implicated in neurodevelopmental disorders characterized by abnormal neural circuitry such as Fragile X syndrome (FXS). In animal models of FXS, the loss in expression of the Fragile X mental retardation 1 protein (FMRP) from astrocytes is associated with delayed dendrite maturation and improper synapse formation; however, the effect of astrocyte-derived factors on the development of neurons is not known. Thrombospondin-1 (TSP-1) is an important astrocyte-secreted protein that is involved in the regulation of spine development and synaptogenesis. In this study, we found that cultured astrocytes isolated from an Fmr1 knockout (Fmr1 KO) mouse model of FXS displayed a significant decrease in TSP-1 protein expression compared to the wildtype (WT) astrocytes. Correspondingly, Fmr1 KO hippocampal neurons exhibited morphological deficits in dendritic spines and alterations in excitatory synapse formation following long-term culture. All spine and synaptic abnormalities were prevented in the presence of either astrocyte-conditioned media or a feeder layer derived from FMRP-expressing astrocytes, or following the application of exogenous TSP-1. Importantly, this work demonstrates the integral role of astrocyte-secreted signals in the establishment of neuronal communication and identifies soluble TSP-1 as a potential therapeutic target for Fragile X syndrome.

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  • Secretion of TSP-1 is abnormally reduced from Fmr1 KO astrocytes, whereas NT-3 levels are increased in the secretome of Fmr1 KO astrocytes and in the Fmr1 KO prefrontal cortex compared with controls.

    “Secretion of thrombospondin-1 (TSP-1) that as an extracellular matrix protein may induce cell adherence and induce synaptogenesis is also abnormally reduced from Fmr1 KO astrocytes (Cheng et al., 2016), whereas neurotrophin-3 (NT-3) levels are increased in the secretome of Fmr1 KO astrocytes as well as in the Fmr1 KO prefrontal cortex when compared with controls (Yang et al., 2012).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Cheng et al., 2016

  • Dendritic spine immaturity and synaptic protein abnormalities of Fmr1 KO neurons are prevented by WT astrocyte conditioned media or a WT feeder layer.

    “Dendritic spine immaturity (relatively increased length) and synaptic protein abnormalities of Fmr1 KO neurons are prevented by WT astrocyte conditioned media or a WT feeder layer (Cheng et al., 2016).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Cheng et al., 2016

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Cited by

Sorted by citations

Authors
Cheng, C., Lau, S. K. M., & Doering, L. C.
Affiliations
McMaster University (CA)
Corresponding author
  • Cheng, Connie
  • Lau, Sally K. M.
  • Doering, Laurie C.
ORCID
Cheng, Connie
Venue
Molecular Brain
Publisher
Springer Science and Business Media LLC
Published
2016-08-02
Volume
9
Issue
1
Pages
74-74
ISSN
1756-6606 (ISSN-L)
DOI
10.1186/s13041-016-0256-9
PMC
PMC4971702
OpenAlex
W2479769265
Cited by
84
References
10
Citations by year
2026: 9 · 2025: 10 · 2024: 15 · 2023: 8 · 2022: 7 · 2021: 11 · 2020: 5 · 2019: 6 · 2018: 6 · 2017: 7
FWCI
5.12
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Brain (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Natural Sciences and Engineering Research Council of Canada
  • Fragile X Research Foundation of Canada
  • Brain Canada/Azrieli Neurodevelopmental Research Program
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
thrombospondin-1, astrocytes, fragile X syndrome, FMRP, dendritic spines, synaptogenesis, astrocyte-neuron communication, Fmr1 knockout mice, hippocampal neurons, therapeutic target
MeSH terms
Animals, Astrocytes, Dendrites, Disease Models, Animal, Female, Fragile X Syndrome, Hippocampus, Male, Spine, Synapses, Culture Media, Conditioned, Mice, Knockout, Thrombospondin 1, Feeder Cells

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