Reduced cell number in the neocortical part of the human fetal brain in Down syndrome
Abstract
Mental retardation is seen in all individuals with Down syndrome (DS) and different brain abnormalities are reported. The aim of this study was to investigate if mental retardation at least in part is a result of a lower cell number in the neocortical part of the human fetal forebrain. We therefore compared brains of DS fetuses aged 19 weeks of gestation with normal control brains. The cell numbers were estimated using the optical fractionator method. The total cell number in the neocortical part of four DS human fetal forebrain was found to be substantially smaller in DS compared to the normal fetus. The average total cell number of 6.85 billion was equal to a reduction by 34% compared to the 10.4 billion cells in a normal fetal brain of that age. This study indicates that the mental retardation found in DS is based on a structural deficit in the human fetal brain already present in the second trimester.
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Trisomy 21 causes complex spatiotemporal disturbances in neural development.
“Morphometric and cellular studies on human brain indicate that trisomy 21 causes complex spatiotemporal disturbances in neural development (Golden and Hyman, 1994; Larsen et al., 2008; Reeves and Haydar, 2011).”
From Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination (2016) · cites this paper as Larsen et al., 2008
The fetal cortex, cerebellum and hippocampus have all been shown to contain fewer neurons in individuals with Down syndrome than in controls, albeit based on small sample sizes.
“The fetal cortex, cerebellum and hippocampus have all been shown to contain fewer neurons in individuals with DS than in controls40–48, albeit based on small sample sizes17.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [45]
At 19 weeks gestation, a significant decrease in total cells was found in the forebrain of fetuses with Down syndrome.
“At 19 weeks gestation, a significant decrease in total cells was found the forebrain (Larsen et al., 2008).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Larsen et al., 2008
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“In 19-week-old DS fetuses, reduction of 34% in the number of neocortical cells was detected despite the lack of morphological and cell density differences compared with controls (Larsen et al., 2008).”
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“…in the adult neocortex of DS is permanent, it is likely the consequence of uncompensated developmental deficits evident as early as the 19th gestational week at which time there are 34% fewer neocortical cells in the forebrain as compared with normal brains as reported by Larsen et al. (2008).”
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ResultSilencing Trisomy 21 with XIST in Neural Stem Cells Promotes Neuronal Differentiation
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“In addition, many of the molecular and cellular perturbations in our neural lines with T21 agree with an altered cellular composition, impaired trophic interactions and deficient functional neural circuits observed in DS brains [7].”
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Klein, J. A., & Haydar, T. F. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.941855 · Cited by 47 · see citing works
“At 19 weeks gestation, a significant decrease in total cells was found the forebrain (Larsen et al., 2008).”
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Altered patterning of trisomy 21 interneuron progenitors
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“In fact, reduced neuron density has been reported in fetal DS brain (Golden and Hyman, 1994; Guidi et al., 2018; Larsen et al., 2008; Schmidt-Sidor et al., 1990; Stagni et al., 2018).”
BackgroundNon‐neuronal cell responses differ between normal and Down syndrome developing brains
Kanaumi, T., Milenković, I., Adle‐Biassette, H., Aronica, E., & Kovács, G. G. (2013) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2013.09.011 · Cited by 39 · see citing works
“Indeed, DS brains show decreased neuronal and glial cell numbers, reduced cortical volume, and delayed myelination, which may contribute to the pathogenesis of mental retardation (Chapman and Hesketh, 2000; Contestabile et al., 2007; Golden and Hyman, 1994; Guidi et al., 2008; Larsen et al., 2008).”
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“Individuals with Down syndrome are characterized by a reduction of brain volume, with the size of the hippocampus and cerebellum being particularly affected; and several defects in cortical lamination that begin during fetal development (Aylward et al., 1997; Golden & Hyman, 1994; Larsen et al., 2008; Raz et al., 1995…”
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Krivega, M., Stiefel, C. M., & Štorchová, Z. (2022) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2022.10.014 · Cited by 40 · see citing works
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“The number of neurons is reduced in the hippocampus, parahippocampal gyrus, and neocortex of DS fetuses (Guidi et al., 2008; Larsen et al., 2008) and in the cortex of DS children (Wisniewski, 1990).”
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“Introduction Down syndrome (DS), caused by trisomy of chromosome 21 [31, 42], is the most common form of chromosomal abnormality; its prevalence increased between 1979 and 2003 from 9.”
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“Indeed, the number of neurons in the hippocampus, parahippocampal gyrus, cerebellum and neocortex of fetuses, children and adults with DS is reduced [41–45].”
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Li, Z., Klein, J. A., Rampam, S., Kurzion, R., Campbell, N. B., Patel, Y., Haydar, T. F., & Zeldich, E. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.932384 · Cited by 24 · see citing works
“While we identified increased apoptosis as one of the contributing factors to the decreased volume, we hypothesized that changes in neuronal differentiation and cortical expansion, another well-defined phenotype in DS, also contributed to the smaller size of the CS (Schmidt-Sidor et al., 1990; Guidi et al., 2008; Lars…”
BackgroundChallenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome
Lee, S. E., Duran-Martinez, M., Khantsis, S., Bianchi, D., & Guedj, F. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.10.001 · Cited by 23 · see citing works
“In developing brains of fetuses with T21, the number of cells in the subplate, intermediate zone, ventricular and subventricular zones is reduced by a third compared to euploid fetuses [82].”
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Neurogenesis and neuronal differentiation in the postnatal frontal cortex in Down syndrome
Utagawa, E. C., Moreno, D. G., Schafernak, K. T., Arva, N. C., Malek‐Ahmadi, M. H., Mufson, E. J., & Perez, S. E. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01385-w · Cited by 24 · see citing works
“Although many of these processes have been studied during the fetal and prenatal stages of brain development in DS [5, 14, 28, 32, 42, 49, 69, 72, 86], there is a general lack of information on early postnatal brain maturation in DS.”
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“We found reduced neural differentiation of mouse and human DS stem cells; findings were consistent with mouse and human brain studies (Contestabile et al., 2007; Larsen et al., 2008) and in vitro studies using brain-derived human neural progenitors (Bhattacharyya et al.”
ResultRueda, N., Vidal, V., García-Cerro, S., Puente, A., Campa, V. M., Lantigua, S., Narcís, J. O., Bartesaghi, R., & Martínez‐Cué, C. (2020) · Journal of Nutrition · doi:10.1093/jn/nxaa207 · Cited by 17 · see citing works
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“We suppose that the intellectual disability often occurring in DS may arise from a structural deficit in the human fetal brain already present in the second trimester (Larsen et al., 2008).”
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Shaking up the silence: consequences of HMGN1 antagonizing PRC2 in the Down syndrome brain
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“Although fetuin has not been examined in neocortical cells of human fetuses, postmortem examinations of DS fetuses have shown smaller neocortical cell numbers, by around one-third, in DS fetuses at 19 weeks gestation compared to the control group [24].”
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Age- and speed-dependent modulation of gaits in DSCAM2J mutant mice.
Thiry, L., Lemieux, M., & Bretzner, F. (2018) · Journal of Neurophysiology · doi:10.1152/jn.00471.2017 · Cited by 8 · see citing works
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“The neocortical part of fetal DS brain is also hypocellular (Larsen et al., 2008).”
BackgroundEnlargement of neuronal size in rat auditory cortex after prolonged sound exposure.
Lu, H., Chen, S.-T., & Poon, P. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.07.075 · Cited by 7
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Neocortical neuronal production and maturation defects in the TcMAC21 mouse model of Down syndrome
Kurabayashi, N., Fujii, K., Otobe, Y., Hiroki, S., Hiratsuka, M., Yoshitane, H., Kazuki, Y., & Takao, K. (2023) · iScience · doi:10.1016/j.isci.2023.108379 · Cited by 13 · see citing works
“Similar phenotypes are observed in several DS mouse models and fetal DS human brain, 7,14,16,23,37–41 suggesting that mis-regulation of cortical progenitors is a common phenotype, although the Dp16 mouse model shows normal progenitor proliferation and neurogenesis.”
ResultMcClure‐Begley, T. D., Ebmeier, C. C., Ball, K. A., Jacobsen, J. R., Kogut, I., Bilousova, G., Klymkowsky, M. W., & Old, W. M. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/315317 · Cited by 6 · see citing works
“Hypocellularity in fetal (6, 10) and adult DS neocortex (11), and defective lamination in the developing neocortex (12) suggest that atypical neuroanatomical features in adult DS brain originate early in gestation during the critical phase of cortical expansion.”
BackgroundPatthy, Á., Hanics, J., Zachár, G., Kovács, G., Harkany, T., & Alpár, A. (2023) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12887 · Cited by 5 · see citing works
“Down’s syndrome is characterised by reduced neurogenesis [61, 62], an imbalance of the projection neuron/interneuron ratio, and”
BackgroundMoreau, M., Dard, R., Madani, A., Kandiah, J., Kassis, N., Ziga, J., Castiglione, H., Day, S., Bourgeois, T., Matrot, B., et al. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05245-9 · Cited by 4 · see citing works
“These abnormalities were also observed in the brain of human fetuses with DS [1 , 4, 5].”
BackgroundLee, S. E., Baxter, L. L., Duran, M. I., Morris, S. D., Mosley, I. A., Fuentes, K. A., Pennings, J., Guedj, F., & Bianchi, D. W. (2024) · Human Molecular Genetics · doi:10.1093/hmg/ddae160 · Cited by 3 · see citing works
Cellularity Defects Are Not Ubiquitous in the Brains of Fetuses With Down Syndrome
Emili, M., Stagni, F., Bonasoni, M., Guidi, S., & Bartesaghi, R. (2024) · Developmental Neurobiology · doi:10.1002/dneu.22953 · Cited by 3 · see citing works
“Although the study by Larsen et al. may suggest that hypocellularity is a generalized cortical feature of DS (Larsen et al. 2008), the current study shows that it is not so, as revealed by the absence of cellularity differences in the INS and CCX. Additional studies are needed to identify brain…”
Shimizu, R., Ishihara, K., Kawashita, E., Sago, H., Yamakawa, K., Mizutani, K.-I., & Akiba, S. (2020) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2020.12.026 · Cited by 3 · see citing works
Avances Citogenéticos y Neurobiológicos en el Síndrome de Down
Fernández-Alcaraz, C., & Carvajal, F. (2013) · Anales de Psicología · doi:10.6018/analesps.30.1.132231 · Cited by 2 · see citing works
“In particular, reports a fewer number of granule cells in the cerebellum, defects in cortical lamination, reductions in the amount of cortical neurons, presence of malformations in arborizations and dendritic spines and synaptic alterations (Becker, Mito, Takashima & Onodera, 1991; Belichenko et al., 2009; Golden & Hy…”
Cognitive impairments in adult mice with RIP140 overexpression in neural stem cells.
Wang, X.-J., Ren, S., Yu, W.-D., Mu, Q., Ye, S., Cui, C., & Guo, J.-Z. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112777 · Cited by 2 · see citing works
Restoring DSCAM expression rescues neuronal morphology and axon guidance deficits in Down syndromePreprint
Agrawal, M., Kirkise, N., Rygel, K., Sahoo, P. K., Vincent, C. J., Joyner, D., Aguilar-Alvarez, R., Philip, T. R., Dhillon, P. S., Patel, J., et al. (2025) · bioRxiv · doi:10.1101/2025.07.25.666804 · Cited by 1 · see citing works
Cholinotrophic basal forebrain connectome dysfunction in Down syndrome with and without dementia
Moreno-Rodríguez, M., Perez, S. E., Nadeem, M., Head, E., & Mufson, E. J. (2025) · iScience · doi:10.1016/j.isci.2025.113041 · Cited by 1 · see citing works
“15 Frontal cortex (FC) cholinotrophic protein levels in DSD+, DSD-and AMC In DS, the FC, which is innervated by CTBF neurons displays an atypical cortical lamination 55,56 as well as other cellular alterations 57–60 compared to neurotypical developing counterparts.”
Adamo, M., Gayer, M., Jacobs, A., Raynaud, Q., Sebbah, R., Domenicantonio, G. D., Latypova, A., Vionnet, N., Kherif, F., Lutti, A., et al. (2025) · Brain Communications · doi:10.1093/braincomms/fcaf117 · Cited by 1 · see citing works
“88 Together with our results, the existing evidence from the literature supports the notion of cortical volume loss predominantly related to deficient neurogenesis that remains stable over time until neurodegenerative pro-cesses—i.e. Alzheimer’s disease neuropathology prevail.”
Ortiz, A. R. R., Saldarriaga, M. A. B., Villegas, J. C. M., & García-Vallejo, F. (2019) · Gene Regulation · doi:10.5772/intechopen.82446 · Cited by 1 · see citing works
Functional Neurogenomics: A New Approach to Study Cognitive Disability in Down Syndrome Brain
García‐Vallejo, F., Ortiz, A. R. R., Gómez, C. A., Ospina, M. S., Villegas, J. C. M., Gómez, A. S., & Soto, J. (2018) · InTech eBooks · doi:10.5772/intechopen.71057 · Cited by 1 · see citing works
“Indeed, fewer cells and disorganized laminas are evident in the cerebral cortex of DS fetuses from as early as the second trimester of gestation [71, 72].”
BackgroundProgenitor diversity during formation of the mammalian neocortex
Atak, Z., & Haydar, T. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1834625
“These changes in NPC proliferation and survival are correlated with hypocel-lularity across multiple brain structures throughout development (Baburamani et al., 2020), including the significant cell loss observed in the forebrain at 19 weeks gestation (Larsen et al., 2008).”
Sato, T., Baxter, L. L., Adams, A., Bishop, L. A., Guedj, F., & Bianchi, D. W. (2025) · Biology Open · doi:10.1242/bio.062296
“…et al., 1992; Contestabile et al., 2007; Guidi et al., 2008, 2011, 2018; Guihard-Costa et al., 2006; Kitano et al., 2023; Klein and Haydar, 2022; Larsen et al., 2008; Lu et al., 2012; Patkee et al., 2020; Rotmensch et al., 1997; Stagni et al., 2018, 2019, 2020; Tarui et al., 2020; Wisniewski et…”
Role of ubiquitin-specific protease 25 in the pathogenesis of Alzheimer's disease in Down syndrome
Song, B. (2018) · cIRcle (University of British Columbia) · doi:10.14288/1.0371122
“, 2008), cerebellum (Wisniewski, 1990) and neocortex (Larsen et al., 2008), with defective synaptogenesis, connectivity and synaptic plasticity.”
BackgroundQuels traitements pour la trisomie 21
Touraine, R., & de Fréminville, B. (2013) · doi:10.1007/978-2-8178-0385-2_9
Bowman, A. B., Ess, K. C., Kumar, K. K., & Summar, K. L. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-397267-5.00130-8 · Cited by 1 · see citing works
- Authors
- Larsen, K. B., Laursen, H., Græm, N., Samuelsen, G. B., Bogdanovic, N., & Pakkenberg, B.
- Affiliations
- Bispebjerg Hospital (DK)
- Rigshospitalet (DK)
- Corresponding author
- Larsen, Karen Bonde
- Venue
- Annals of Anatomy - Anatomischer Anzeiger
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 190
- Issue
- 5
- Pages
- 421-427
- ISSN
- 0940-9602 (ISSN-L)
- OpenAlex
- W2028537932
- Cited by
- 87
- References
- 0
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 7 · 2023: 5 · 2022: 13 · 2021: 2 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 6 · 2015: 2 · 2014: 1 · 2013: 6 · 2012: 4
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Anatomy - Anatomischer Anzeiger (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Down syndrome, fetal brain, neocortex, cell number, intellectual disability, second trimester
- MeSH terms
- Autopsy, Cell Count, Down Syndrome, Female, Fetus, Gestational Age, Humans, Male, Intellectual Disability, Pregnancy, Pregnancy Trimester, Second, Visual Cortex, Neocortex
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