Down Syndrome iPSC-Derived Astrocytes Impair Neuronal Synaptogenesis and the mTOR Pathway In Vitro
Abstract
Several methods have been used to study the neuropathogenesis of Down syndrome (DS), such as mouse aneuploidies, post mortem human brains, and in vitro cell culture of neural progenitor cells. More recently, induced pluripotent stem cell (iPSC) technology has offered new approaches in investigation, providing a valuable tool for studying specific cell types affected by DS, especially neurons and astrocytes. Here, we investigated the role of astrocytes in DS developmental disease and the impact of the astrocyte secretome in neuron mTOR signaling and synapse formation using iPSC derived from DS and wild-type (WT) subjects. We demonstrated for the first time that DS neurons derived from hiPSC recapitulate the hyperactivation of the Akt/mTOR axis observed in DS brains and that DS astrocytes may play a key role in this dysfunction. Our results bear out that 21 trisomy in astrocytes contributes to neuronal abnormalities in addition to cell autonomous dysfunctions caused by 21 trisomy in neurons. Further research in this direction will likely yield additional insights, thereby improving our understanding of DS and potentially facilitating the development of new therapeutic approaches.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [131]
Gene dysregulation and disrupted calcium signalling in glial cells contribute to the synaptic deficits in DS.
“Evidence suggests that gene dysregulation and disrupted calcium signalling in glial cells also contribute to the synaptic deficits131,134.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [131]
In vitro human iPSC-derived neurons from individuals with DS have reduced excitatory synaptic density relative to controls and functional deficits in excitatory synaptic transmission, including reduced frequency of spontaneous post-synaptic currents.
“In vitro data from human iPSC-derived neurons indicate that neurons from humans with DS not only have reduced excitatory synaptic density relative to controls but also exhibit functional deficits in excitatory synaptic transmission, including reduced frequency of spontaneous post-synaptic currents81,131.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [131]
DS alters the secretome of astrocytes, which exerts a direct impact on synaptogenesis.
“For example, DS has been shown to alter the secretome (the factors secreted by cells) of astrocytes, which exerts a direct impact on synaptogenesis131,144.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [131]
Cites
Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors
Allen, N. J., Bennett, M. L., Foo, L. C., Wang, G. X., Chakraborty, C., Smith, S. J., & Barres, B. A. (2012) · Nature · doi:10.1038/nature11059 · Cited by 764 · see citing works
Dazert, E., & Hall, M. N. (2011) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2011.09.003 · Cited by 460 · see citing works
Chen, C., Jiang, P., Xue, H., Peterson, S. E., Tran, H. T., McCann, A. E., Parast, M. M., Li, S., Pleasure, D. E., Laurent, L. C., et al. (2014) · Nature Communications · doi:10.1038/ncomms5430 · Cited by 219 · see citing works
Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain
Perluigi, M., Pupo, G., Tramutola, A., Cini, C., Coccia, R., Barone, E., Head, E., Butterfield, D. A., & Di Domenico, F. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.04.007 · Cited by 155 · see citing works
Garcia, O., Torres, M., Helguera, P., Coskun, P., & Busciglio, J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014200 · Cited by 122 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ponroy Bally, B., Farmer, W. T., Jones, E. V., Jessa, S., Kacerovsky, J. B., Mayran, A., Peng, H., Lefebvre, J. L., Drouin, J., Hayer, A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa003 · Cited by 49 · see citing works
Astrocytes in Down Syndrome Across the Lifespan
Ponroy Bally, B., & Murai, K. K. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.702685 · Cited by 35 · see citing works
Consequences of trisomy 21 for brain development in Down syndrome
Russo, M. L., Sousa, A. M. M., & Bhattacharyya, A. (2024) · Nature Reviews Neuroscience · doi:10.1038/s41583-024-00866-2 · Cited by 28 · see citing works
“…data from human iPSC-derived neurons indicate that neurons from humans with DS not only have reduced excitatory synaptic density relative to controls but also exhibit functional deficits in excitatory synaptic transmission, including reduced frequency of spontaneous post-synaptic currents 81,131 .”
InfluentialRethinking intellectual disability from neuro- to astro-pathology.
Fernández-Blanco, Á., & Dierssen, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239039 · Cited by 19 · see citing works
- Authors
- Araujo, B. H. S., Kaid, C., De Souza, J. S., Gomes da Silva, S., Goulart, E., Caires, L. C. J., Musso, C. M., Torres, L. B., Ferrasa, A., Herai, R., Zatz, M., Okamoto, O. K., & Cavalheiro, E. A.
- Affiliations
- Universidade de São Paulo (BR)
- Faculdade São Leopoldo Mandic (BR)
- Pontifícia Universidade Católica do Paraná (BR)
- Universidade Estadual de Ponta Grossa (BR)
- ORCID
- Venue
- Molecular Neurobiology
- Published
- 2017-11-11
- Volume
- 55
- Issue
- 7
- Pages
- 5962-5975
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- OpenAlex
- W2767514723
- Cited by
- 56
- References
- 5
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 8 · 2022: 10 · 2021: 9 · 2020: 8 · 2019: 6 · 2018: 2
- FWCI
- 4.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Centros de Pesquisa, Inovação e Difusão (CEPID) (2013/08028-1)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2014/08049-1)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Down syndrome, induced pluripotent stem cells, iPSC-derived astrocytes, iPSC-derived neurons, synaptogenesis, mTOR signaling, Akt/mTOR signaling, astrocyte secretome, neuronal dysfunction, neurodevelopmental disorders
- MeSH terms
- Animals, Astrocytes, Down Syndrome, Humans, Neurons, Synapses, Signal Transduction, Apoptosis, Spheroids, Cellular, Coculture Techniques, Cell Proliferation, Mice, Neurogenesis, Induced Pluripotent Stem Cells, TOR Serine-Threonine Kinases, Neural Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
