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Cited by 192Pluripotent Stem Cells ResearchGenetics and Neurodevelopmental DisordersNeurogenesis and neuroplasticity mechanisms

Human Models Are Needed for Studying Human Neurodevelopmental Disorders

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Zhao, Xinyu, Bhattacharyya, Anita·2018·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2018.10.009PMC PMC6288051
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Abstract

The analysis of animal models of neurological disease has been instrumental in furthering our understanding of neurodevelopment and brain diseases. However, animal models are limited in revealing some of the most fundamental aspects of development, genetics, pathology, and disease mechanisms that are unique to humans. These shortcomings are exaggerated in disorders that affect the brain, where the most significant differences between humans and animal models exist, and could underscore failures in targeted therapeutic interventions in affected individuals. Human pluripotent stem cells have emerged as a much-needed model system for investigating human-specific biology and disease mechanisms. However, questions remain regarding whether these cell-culture-based models are sufficient or even necessary. In this review, we summarize human-specific features of neurodevelopment and the most common neurodevelopmental disorders, present discrepancies between animal models and human diseases, demonstrate how human stem cell models can provide meaningful information, and discuss the challenges that exist in our pursuit to understand distinctively human aspects of neurodevelopment and brain disease. This information argues for a more thoughtful approach to disease modeling through consideration of the valuable features and limitations of each model system, be they human or animal, to mimic disease characteristics.

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  • Human induced pluripotent stem cells generated from somatic cells of individuals with Down syndrome provide another approach to interrogate the cellular and molecular mechanisms underlying altered neural development in human cells.

    “Human induced pluripotent stem cells (iPSCs) generated from somatic cells of individuals with DS provide another approach to interrogate the cellular and molecular mechanisms underlying altered neural development in human cells28 (Boxes 1 and 2).”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [28]

  • Murine systems have limited translational relevance to human-specific aspects of neurodevelopment and cortical circuitry.

    “Despite advances in modeling Ts21, murine systems have limited translational relevance to human-specific aspects of neurodevelopment and cortical circuitry (7), whereas stem cell models have faced inherent constraints in recapitulating in vivo cellular diversity and the organization of neuronal-glial interactions (8, 9).”

    From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [7]

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References 390 · Cited by 192

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Authors
Zhao, X., & Bhattacharyya, A.
Affiliations
University of Wisconsin–Madison (US)
Corresponding author
  • Zhao, Xinyu
  • Bhattacharyya, Anita
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2018-12
Volume
103
Issue
6
Pages
829-857
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2018.10.009
PMC
PMC6288051
OpenAlex
W2905427486
Cited by
192
References
390
Citations by year
2026: 21 · 2025: 35 · 2024: 32 · 2023: 26 · 2022: 35 · 2021: 24 · 2020: 15 · 2019: 4
FWCI
1.05
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (R01MH078972, 1R01MH116582, R56MH113146, R21HD085288, R03HD083538, R21NS105339, U54HD090256)
  • University of Wisconsin-Madison
  • Wisconsin Alumni Research Foundation
  • Jenni and Kyle Professorship
  • John Merck Fund
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
neurodevelopmental disorders, human pluripotent stem cells, animal models of neurological disease, animal model limitations, disease modeling
MeSH terms
Animals, Brain, Humans, Models, Biological, Cell Culture Techniques, Induced Pluripotent Stem Cells, Neurodevelopmental Disorders

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 ›

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