Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model
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Abstract
Abstract Down syndrome (DS) is a devastating genetic disorder causing severe cognitive impairment. The staggering array of effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We developed an in vitro system to examine the interplay of neurons and astrocytes in a fully recapitulated HSA21 trisomy model differentiated from DS patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we utilized this system to investigate the functional defects of DS astroglia and their effects on neuronal excitability. We found that, compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. DS astrocytes exerted this effect on both DS and healthy neurons. Neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated astrocyte–neuron signaling or genetically by knockdown of inositol triphosphate (IP 3 ) receptors or S100β, a calcium binding protein coded on HSA21. Our results suggest a novel mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability. Furthermore, our study establishes an all-optical neurophysiological platform for studying human neuron-astrocyte interactions associated with neurological disorders. Significant statement Down syndrome (DS) is the most common genetic disorder caused by trisomy of chromosome 21 (HSA21). Problems with cognitive impairment, have not been properly addressed due to the inability to fully recapitulate HSA21, which is further confounded by the snapshot views of morphological changes of brain cells in isolation obtained from current studies. The brain develops neural networks consisting of neurons and glial cells that work together. To understand how DS affects the neural networks, we used DS patient-derived stem cells and calcium imaging to investigate functional defects of DS astrocytes and their effects on neuronal excitability. Our study has significant implication in understanding functional defects during brain development underlying DS.
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Astrocytes and microglia have a role in the DS synaptic phenotype.
“Although the tools used to ensure accurate proportions of interneuron subtypes in a culture system have only recently been developed132, simple neuron–glia co-cultures have already provided evidence that astrocytes and microglia do have a role in the DS synaptic phenotype131,134,135.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [135]
The Results section, “DS Astroglia Promote Synaptic Connectivity,” reports that neurons co-cultured with Down syndrome astroglia had increased postsynaptic current amplitudes and synapse density, supporting an astrocyte role in the synaptic phenotype. The paper’s neuron–astroglia co-cultures do not establish the claimed role for microglia. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCo-culture with T21 iPSC-derived astrocytes reduces the intrinsic excitability of neurons and tends to have a consequent impact on synaptic development and transmission.
“Co-culture with T21 iPSC-derived astrocytes also reduces the intrinsic excitability of neurons and tends to have a consequent impact on synaptic development and transmission82,135,145.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [135]
The Results section, “DS Astroglia Inhibit the Excitability of Co-cultured Neurons” (page unavailable), reports reduced evoked neuronal activity with trisomy 21 iPSC-derived astroglia. “DS Astroglia Promote Synaptic Connectivity” reports increased synapse density and mEPSC amplitude. The paper describes reduced global excitability and associated synaptic changes, but does not establish that intrinsic neuronal excitability was reduced or that its reduction caused the synaptic changes. (LLM, conf=0.85)
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“Co-culture with T21 iPSC-derived astrocytes also reduces the intrinsic excitability of neurons and tends to have a consequent impact on synaptic development and transmission 82,135,145 .”
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- Authors
- Mizuno, G. O., Wang, Y., Shi, G., Wang, Y., Sun, J., Papadopoulos, S., Broussard, G. J., Unger, E. K., Deng, W., Weick, J., Bhattacharyya, A., Chen, C.-Y., Yu, G., Looger, L. L., & Tian, L.
- Affiliations
- University of California, Davis (US)
- Virginia Tech (US)
- University of New Mexico (US)
- University of Wisconsin–Madison (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Tian, Lin
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 24
- Issue
- 2
- Pages
- 355-365
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6631348
- OpenAlex
- W2791218687
- Cited by
- 58
- References
- 55
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 6 · 2023: 11 · 2022: 7 · 2021: 8 · 2020: 10 · 2019: 6
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- VTechWorks (Virginia Tech) (submittedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R21NS093442-01, NSF7566685)
- National Institute of General Medical Sciences (1P20GM109089-01A1)
- National Institute on Deafness and Other Communication Disorders
- Hartwell Foundation
- National Institutes of Health (NSF1750931, DP2MH107056, R21NS095325, R01MH110504, R03 HD064880)
- University of California, Davis
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Down syndrome, astrocytes, neuronal excitability, calcium signaling, astrocyte-neuron interaction, induced pluripotent stem cells, adenosine signaling, IP3 receptor, S100B, cognitive impairment
- MeSH terms
- Animals, Astrocytes, Calcium, Cell Differentiation, Down Syndrome, Endoplasmic Reticulum, Humans, Models, Biological, S100 Proteins, Neurons, Synapses, Calcium Signaling, Imaging, Three-Dimensional, Inositol 1,4,5-Trisphosphate Receptors, Induced Pluripotent Stem Cells
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