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Astrocytes mediate cell non-autonomous correction of aberrant firing in human FXS neurons.

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Sharma, Shreya Das, Reddy, Bharath Kumar, Pal, Rakhi, Ritakari, Tuula E., Cooper, James D., Selvaraj, Bhuvaneish T., Kind, Peter C., Chandran, Siddharthan +2 more·2023·Cell Reports
DOI 10.1016/j.celrep.2023.112344PMC PMC10157295
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Abstract

Pre-clinical studies of fragile X syndrome (FXS) have focused on neurons, with the role of glia remaining largely underexplored. We examined the astrocytic regulation of aberrant firing of FXS neurons derived from human pluripotent stem cells. Human FXS cortical neurons, co-cultured with human FXS astrocytes, fired frequent short-duration spontaneous bursts of action potentials compared with less frequent, longer-duration bursts of control neurons co-cultured with control astrocytes. Intriguingly, bursts fired by FXS neurons co-cultured with control astrocytes are indistinguishable from control neurons. Conversely, control neurons exhibit aberrant firing in the presence of FXS astrocytes. Thus, the astrocyte genotype determines the neuronal firing phenotype. Strikingly, astrocytic-conditioned medium, and not the physical presence of astrocytes, is capable of determining the firing phenotype. The mechanistic basis of this effect indicates that the astroglial-derived protein, S100β, restores normal firing by reversing the suppression of a persistent sodium current in FXS neurons.

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  • FXS neurons showed a high frequency of short, spontaneous bursts and reduced persistent Na+ current in the presence of FXS astrocytes or media secreted by FXS astrocytes.

    “FXS neurons showed a high frequency of short, spontaneous bursts and reduced persistent Na+ current in the presence of FXS astrocytes or media secreted by FXS astrocytes.”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Das Sharma et al., 2023

    The Results sections on astrocyte genotype and conditioned medium report frequent, short spontaneous bursts in FXS neurons with FXS astrocytes or FXS astrocyte-conditioned medium. The section on persistent sodium currents reports reduced INaP in FXS neurons co-cultured with FXS astrocytes, but does not establish that reduction for neurons grown in conditioned medium. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Astrocyte-specific Ca2+ binding protein S100B prevents abnormalities of Na+ current and firing pattern in FXS and control neurons co-cultured with FXS astrocytes or FXS astrocyte-derived conditioned medium.

    “Astrocyte-specific Ca2+ binding protein S100B was found to prevent abnormalities of Na+ current and firing pattern in FXS and control neurons co-cultured with FXS astrocytes or FXS astrocyte-derived conditioned medium.”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Das Sharma et al., 2023

    The Results section (page not provided) reports that adding S100β restored persistent sodium current and normal firing in both FXS and control neurons co-cultured with FXS astrocytes. It also reports that FXS astrocyte-conditioned medium can induce abnormal firing, but does not show that adding S100β corrects neurons exposed to that medium. The demonstrated effect was reversal of existing abnormalities, rather than prevention. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The role of FXS astrocytes in abnormal neuronal firing was confirmed in co-cultures of cortical neurons and astrocytes derived from human stem cells generated from patients with FXS and a control donor.

    “The role of FXS astrocytes in abnormal neuronal firing was recently confirmed in co-cultures of cortical neurons and astrocytes derived from human stem cells generated from patients with FXS and a control donor (Das Sharma et al., 2023).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Das Sharma et al., 2023

  • Blocking antibody to S100B induces disordered firing in co-cultures of control neurons and control astrocytes, demonstrating that astrocyte secreted factors can influence firing patterns of glutamatergic neurons.

    “Furthermore, blocking antibody to S100B induced disordered firing in co-cultures of control neurons and control astrocytes (Das Sharma et al., 2023), demonstrating that astrocyte secreted factors can influence the firing patterns of glutamatergic neurons (Das Sharma et al., 2020).”

    From Astrocytes in fragile X syndrome (2024) · cites this paper as Das Sharma et al., 2023

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Cited by

Sorted by citations

  • Astrocytes in fragile X syndrome

    Talvio, K., & Castrén, M. L. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1322541 · Cited by 8 · see citing works

    “Furthermore, blocking antibody to S100B induced disordered firing in co-cultures of control neurons and control astrocytes (Das Sharma et al., 2023), demonstrating that astrocyte secreted factors can influence the firing patterns of glutamatergic neurons (Das Sharma et al., 2020).”
    Background

Authors
Sharma, S. D., Reddy, B. K., Pal, R., Ritakari, T. E., Cooper, J. D., Selvaraj, B. T., Kind, P. C., Chandran, S., Wyllie, D. J. A., & Chattarji, S.
Affiliations
  • Tata Institute of Fundamental Research (IN)
  • UK Dementia Research Institute (GB)
  • Institute for Stem Cell Biology and Regenerative Medicine (IN)
Corresponding author
  • Wyllie, David J.A.
  • Chattarji, Sumantra
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2023-04
Volume
42
Issue
4
Pages
112344
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2023.112344
PMC
PMC10157295
OpenAlex
W4362601021
Cited by
31
References
6
Citations by year
2026: 11 · 2025: 8 · 2024: 8 · 2023: 3 · 2022: 1
FWCI
4.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
  • Simons Foundation
  • Simons Foundation Autism Research Initiative (529085)
  • Medical Research Council
  • Government of India Department of Biotechnology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
Keywords
fragile X syndrome, astrocytes, neuronal firing, astrocyte-neuron co-culture, astrocyte-conditioned medium, S100β, persistent sodium current, human pluripotent stem cell-derived neurons
MeSH terms
Astrocytes, Fragile X Syndrome, Humans, Neurons, Coculture Techniques, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein

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