In vivo modeling of human neuron dynamics and Down syndrome
Open accessAbstract
Development of human brain neurons: The earliest stages of human brain development are very difficult to monitor, but using induced pluripotent stem cells (iPSCs) can help to elucidate the process. Real et al. transplanted neural progenitors derived from human iPSCs into the brains of adult mice. They used intravital imaging to visualize how resulting neurons grew and connected. The human cells produced neurons that integrated and developed synaptic networks with oscillatory activity. Dendritic pruning was observed and involved a process of branch retraction, not degeneration. Cells derived from individuals with Down syndrome, upon transplantation into the mouse brain, produced neurons that grew normally but showed reduced dendritic spine turnover and less network activity. Science , this issue p. eaau1810
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PSC-derived human cortical neurons transplanted as bulk cell populations displayed rapid dendritic spine turnover throughout the experiment and reached very limited levels of synaptic connectivity with the host brain.
“This contrasts with recent findings in PSC-derived human cortical neurons transplanted as bulk cell populations, which displayed rapid dendritic spine turnover throughout the experiment (spine half-life <4 days versus 2 weeks at 3–4 months), and reached very limited levels of synaptic connectivity with the host brain (Real et al., 2018).”
From Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits (2019) · cites this paper as Real et al., 2018
In “Human synaptic development imaged in vivo” (page unavailable), the paper reports substantial spine turnover at 3 months, but lower turnover at 4 months; it could not quantify spine dynamics before 3 months. It does not establish a spine half-life of less than 4 days throughout the experiment. “Functional human cortical networks imaged in vivo” (page unavailable) supports limited host input: tracing found that 7.5% ± 1.5% of inputs came from host neurons. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTrisomic neuronal grafts show fewer bursting activity and reduced bursting frequency.
“Fewer trisomic grafts exhibited bursting activity and those that did had reduced bursting frequency (Real et al., 2018).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Real et al., 2018
The section “Imaging human neuron structural and functional dynamics in Down syndrome” (page unavailable) reports reduced burst activity in Ts21 grafts. It does not specify that fewer grafts exhibited bursts or that the grafts which did burst had a lower bursting frequency. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAlterations in circuitry rather than intrinsic neuronal properties may be responsible for altered neuronal activity.
“These activity changes indicate that it may be alterations in circuitry rather than changes in intrinsic neuronal properties that may be responsible for altered neuronal activity.”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Real et al., 2018
The section “Imaging human neuron structural and functional dynamics in Down syndrome” reports reduced burst and global activity in trisomy 21 grafts, supporting the network-activity part of the claim. The Conclusion describes cell-intrinsic deficits, but the paper does not establish that circuitry changes, rather than changes in intrinsic neuronal properties, caused the altered activity. Page numbers were not provided in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredA recent study using in vivo imaging showed limited synaptic integration of human cortical pyramidal neurons in the mouse cortex.
“A recent study using in vivo imaging showed limited synaptic integration of human cortical pyramidal neurons in the mouse cortex”
From Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits (2019) · cites this paper as Real et al., 2018
In xenografts of human iPSC-derived neurons into mouse brain, T21 neurons exhibit reduced network activity relative to control neurons.
“More recently, xenografts of human iPSC-derived neurons into mouse brain revealed that, although both control neurons and T21 neurons can successfully incorporate into the mouse brain by forming synapses with the surrounding mouse neurons, T21 neurons exhibit reduced network activity relative to control neurons133.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [133]
When DS iPSC-derived neurons are transplanted into the mouse brain, they have reduced structural plasticity relative to controls.
“Moreover, neurons generated from iPSCs derived from individuals with DS have little to no capacity for either LTP or LTD in vitro132, and when transplanted into the mouse brain, these neurons have reduced structural plasticity relative to controls133.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [133]
Engrafted trisomic neurons show increased spine density.
“A novel study where NPCs and neurons derived from iPSCs were engrafted into mouse cortex and allowed to mature found an increase in spine density in the trisomic neurons compared to euploid controls (Real et al., 2018).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Real et al., 2018
Trisomic neurons have more stable spines with less turnover.
“The spines on the trisomic neurons also appeared to be more stable, with less turnover observed in trisomic neurons compared to euploid.”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Real et al., 2018
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 [29]
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Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer’s Disease
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In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration
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Studying human neural function in vivo at the cellular level: Chasing chimeras?
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Neuronal Cell-Intrinsic Defects in Mouse Models of Down Syndrome
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Studying Abnormal Chromosomal Diseases Using Patient-Derived Induced Pluripotent Stem Cells
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Circuit integration by transplanted human neurons
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iPSCs-Derived Neurons and Brain Organoids from Patients
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An In Vivo Platform for Rebuilding Functional Neocortical Tissue
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Self and the Brain. The Immune Metaphor
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Neurodevelopmental disorders: 2023 update
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Synaptic and intrinsic membrane defects disrupt early neural network dynamics in Down syndrome
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Seeking clarity on sex differences in cardiovascular complications of Down syndrome
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Trisomy 21 Impairs Synchronized Activity in Human Down Syndrome Cortical Excitatory Neuron NetworksPreprint
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Emerging Methods in Modeling Brain Development and Disease with Human Pluripotent Stem Cells
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- Authors
- Real, R., Peter, M., Trabalza, A., Khan, S., Smith, M. A., Dopp, J., Barnes, S. J., Momoh, A., Strano, A., Volpi, E., Knott, G., Livesey, F. J., & De Paola, V.
- Affiliations
- Universidade do Porto (PT)
- University of Cambridge (GB)
- Imperial College London (GB)
- UK Dementia Research Institute (GB)
- University of Westminster (GB)
- École Polytechnique Fédérale de Lausanne (CH)
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
- Corresponding author
- Real, Raquel
- Peter, Manuel
- Trabalza, Antonio
- Livesey, Frederick J.
- ORCID
- Venue
- Science
- Published
- 2018-11-16
- Volume
- 362
- Issue
- 6416
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6570619
- OpenAlex
- W2896561023
- Cited by
- 120
- References
- 60
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 12 · 2023: 16 · 2022: 22 · 2021: 15 · 2020: 24 · 2019: 10 · 2018: 4
- FWCI
- 6.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- WestminsterResearch (University of Westminster) (acceptedVersion)
- Lirias (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Spiral (Imperial College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- Down syndrome, in vivo imaging, synaptic stability, neural oscillations, cortical development, patient-specific modeling
- MeSH terms
- Animals, Axons, Cerebral Cortex, Down Syndrome, Humans, Models, Biological, Neuroglia, Neuronal Plasticity, Neurons, Synapses, Mice, SCID, Microscopy, Fluorescence, Multiphoton, Mice, Neurogenesis, Induced Pluripotent Stem Cells, Neural Stem Cells, Single-Cell Analysis, Neuroimaging
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