Neuronal Cell-Intrinsic Defects in Mouse Models of Down Syndrome
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Down Syndrome (DS) is the most common genetic disorder associated with intellectual disability (ID). Excitatory neurons of DS patients and mouse models show decreased size of dendritic field and reduction of spine density. Whether these defects are caused by cell autonomous alterations or by abnormal multicellular circuitry is still unknown. In this work, we explored this issue by culturing cortical neurons obtained from two mouse models of DS: the widely used Ts65Dn and the less characterized Ts2Cje. We observed that, in the in vitro conditions, axon specification and elongation, as well as dendritogenesis, take place without evident abnormalities, indicating that the initial phases of neuronal differentiation do not suffer from the presence of an imbalanced genetic dosage. Conversely, our analysis highlighted differences between trisomic and euploid neurons in terms of reduction of spine density, in accordance with in vivo data obtained by other groups, proposing the presence of a cell-intrinsic malfunction. This work suggests that the characteristic morphological defects of DS neurons are likely to be caused by the possible combination of cell-intrinsic defects together with cell-extrinsic cues. Additionally, our data support the possibility of using the more sustainable line Ts2Cje as a standard model for the study of DS.
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Recent studies using complementary mouse models of DS (Ts65Dn, Ts2Cje, Tc1, Dp16) reported an activated microglia phenotype during brain development, with functional morphological alterations and elevated pro-inflammatory cytokines, accompanied by a reduction of neuronal dendritic spines.
“Recent studies using complementary mouse models of DS, including Ts65Dn, Ts2Cje, Tc1, and Dp16 mice, reported an activated phenotype in microglia cells during brain development, as evidenced by functional morphological alterations and elevated pro-inflammatory cytokines, accompanied by a reduction of neuronal dendritic spines.26,27,28,29”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [27]
The Results section, “Dendritic Spines of Trisomic Neurons in Primary Culture Show Immature Morphology and Reduced Density” (page unavailable), reports reduced spine density in Ts65Dn and Ts2Cje cortical neurons. The paper does not report activated microglia, elevated pro-inflammatory cytokines, or findings from Tc1 and Dp16 mice; searches for microglia and those models found no supporting passage. (LLM, conf=0.90)
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Palmer, C. R., Liu, C. S., Romanow, W. J., Lee, M.-H., & Chun, J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2114326118 · Cited by 89 · see citing works
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- Authors
- Chiotto, A. M. A., Migliorero, M., Pallavicini, G., Bianchi, F. T., Gai, M., Di Cunto, F., & Berto, G. E.
- Affiliations
- Neuroscience Institute Cavalieri Ottolenghi (IT)
- University of Turin (IT)
- Corresponding author
- Berto, Gaia Elena
- Venue
- Frontiers in Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2019-10-10
- Volume
- 13
- Pages
- 1081-1081
- ISSN
- 1662-453X (ISSN-L)
- PMC
- PMC6795679
- OpenAlex
- W2980151119
- Cited by
- 9
- References
- 5
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2022: 2 · 2021: 3
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fondation Jérôme Lejeune
- 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
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Keywords
- Down syndrome, Ts65Dn mouse model, trisomy, intellectual disability, cortical neurons, dendritic field size, dendritic spine density, axon specification, dendritogenesis, neuronal differentiation, neuronal morphology
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