RESEARCH ARTICLE: Neurogenesis Impairment and Increased Cell Death Reduce Total Neuron Number in the Hippocampal Region of Fetuses with Down Syndrome
Open accessAbstract
We previously obtained evidence for reduced cell proliferation in the dentate gyrus (DG) of fetuses with Down syndrome (DS), suggesting that the hippocampal hypoplasia seen in adulthood may be caused by defective early neuron production. The goal of this study was to establish whether DS fetuses (17–21 weeks of gestation) exhibit reduction in total cell number in the DG, hippocampus and parahippocampal gyrus (PHG). Volumes of the cellular layers and cell number were estimated with Cavalieri's principle and the optical fractionator method, respectively. We found that in DS fetuses all investigated structures had a reduced volume and cell number. Analysis of cell phenotype showed that DS fetuses had a higher percentage of cells with astrocytic phenotype but a smaller percentage of cells with neuronal phenotype. Immunohistochemistry for Ki‐67, a marker of cycling cells, showed that DS fetuses had less proliferating cells in the germinal zones of the hippocampus and PHG. We additionally found that in the hippocampal region of DS fetuses there was a higher incidence of apoptotic cell death. Results show reduced neuron number in the DS hippocampal region and suggest that this defect is caused by disruption of neurogenesis and apoptosis, two fundamental processes underlying brain building.
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?
Astrocyte number, usually measured by immunostaining for glial fibrillary acidic protein, is often assessed relative to the number of neurons, which means that an increase could reflect decreased numbers of neurons or increased numbers of astrocytes.
“However, astrocyte number, usually measured by immunostaining for glial fibrillary acidic protein (GFAP), is often assessed relative to the number of neurons, which means that this increase could reflect decreased numbers of neurons or increased numbers of astrocytes42.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [42]
The presence of fewer cycling cells and the reduced number of progenitors both support the suggestion that neurogenesis is reduced during development in Down syndrome, although these data do not distinguish between slower progenitor proliferation or premature progenitor cell cycle exit.
“Together, the presence of fewer cycling cells and the reduced number of progenitors both support the suggestion that neurogenesis is reduced during development in DS, although these data do not distinguish between slower progenitor proliferation or premature progenitor cell cycle exit.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [42]
Increased numbers of astrocytes have been reported in the fetal brain in individuals with Down syndrome.
“Increased numbers of astrocytes have been reported in the fetal brain in individuals with DS42,44,99 (Fig. 1).”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [42]
Analyses of fetal brain tissue indicate that there are fewer proliferating cells, as measured by expression of the cell cycle marker Ki67 and of cyclin proteins, in the germinal zones of the hippocampus and cortex in Down syndrome.
“Analyses of fetal brain tissue indicate that there are fewer proliferating cells, as measured by their expression of the cell cycle marker Ki67 and of cyclin proteins, in the germinal zones of the hippocampus and cortex in DS40,42–44,47,50,64.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [42]
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 [42]
During 17-21 weeks gestation, fewer neurons were found in the hippocampus, cerebellum, and multiple thalamic nuclei in fetuses with Down syndrome.
“During the same time period (17–21 weeks gestation) fewer neurons were found in the hippocampus (Guidi et al., 2008), cerebellum (Guidi et al., 2011), and multiple thalamic nuclei (Stagni et al., 2020).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Guidi et al., 2008
Cites
Unbiased stereological estimation of the number of neurons in the human hippocampus
West, M. J., & Gundersen, H. J. G. (1990) · Journal of Comparative Neurology · doi:10.1002/cne.902960102 · Cited by 1,153 · cited 1× · see citing works
“Based on the Cavalieri principle (17, 52), we estimated the reference volume (Vref) of the granule cell layer, pyramidal layer, lamina principalis interna and lamina principalis externa of the PRES and EC and single cellular lamina of the LPHG by multiplying the sum of the areas measured in the series of sections by t…”
MethodNeuroanatomy of Down’s Syndrome: A High-Resolution MRI Study
Pinter, J. D., Eliez, S., Schmitt, J. E., Capone, G. T., & Reiss, A. L. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.10.1659 · Cited by 452 · see citing works
Carlesimo, G. A., Marotta, L., & Vicari, S. (1997) · Neuropsychologia · doi:10.1016/s0028-3932(96)00055-3 · Cited by 211 · see citing works
Down's syndrome: Is there a decreased population of neurons?
Ross, M. H., Galaburda, A. M., & Kemper, T. L. (1984) · Neurology · doi:10.1212/wnl.34.7.909 · Cited by 191 · see citing works
ets-2 Promotes the Activation of a Mitochondrial Death Pathway in Down's Syndrome Neurons
Helguera, P., Pelsman, A., Pigino, G., Wolvetang, E., Head, E., & Busciglio, J. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.5107-04.2005 · Cited by 88 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Dementia in Down syndrome: unique insights for Alzheimer disease research
Lott, I. T., & Head, E. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-018-0132-6 · Cited by 383 · see citing works
Nurturing brain plasticity: Impact of environmental enrichment
Baroncelli, L., Braschi, C., Spolidoro, M., Begenisic, T., Sale, A., & Maffei, L. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.193 · Cited by 330 · see citing works
Neurological phenotypes for Down syndrome across the life span
Lott, I. T. (2012) · Progress in Brain Research · doi:10.1016/b978-0-444-54299-1.00006-6 · Cited by 225 · 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
MNB/DYRK1A as a multiple regulator of neuronal development
Tejedor, F. J., & Hämmerle, B. (2011) · The FEBS Journal · doi:10.1111/j.1742-4658.2010.07954.x · Cited by 214 · see citing works
Duchon, A., & Herault, Y. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00104 · Cited by 181 · see citing works
Bianchi, P., Ciani, E., Guidi, S., Trazzi, S., Felice, D., Grossi, G., Fernandez, M., Giuliani, A., Calza, L., & Bartesaghi, R. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0534-10.2010 · Cited by 188 · see citing works
Self-citationForm and function of sleep spindles across the lifespan
Clawson, B. C., Durkin, J., & Aton, S. J. (2016) · Neural Plasticity · doi:10.1155/2016/6936381 · Cited by 178 · see citing works
“For example, childrenwithDown syndrome show decreased proliferation of neuronal progenitor cells during gestation, decreased mature neuronal numbers overall, decreased dendritic spine density, changes in LTP and LTD, and early-onset neurodegeneration when compared with typically developing children [129–131].”
BackgroundHibaoui, Y., Grad, I., Letourneau, A., Sailani, M. R., Dahoun, S., Santoni, F. A., Gimelli, S., Guipponi, M., Pelte, M. F., Béna, F., et al. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201302848 · Cited by 170 · see citing works
Down syndrome and dementia: A randomized, controlled trial of antioxidant supplementation
Lott, I. T., Doran, E., Nguyen, V. Q., Tournay, A., Head, E., & Gillen, D. L. (2011) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.34114 · Cited by 136 · see citing works
Communication breaks-Down: From neurodevelopment defects to cognitive disabilities in Down syndrome
Contestabile, A., Benfenati, F., & Gasparini, L. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.01.003 · Cited by 134 · see citing works
Huo, H.-Q., Qu, Z.-Y., Yuan, F., Ma, L., Yao, L., Xu, M., Hu, Y., Ji, J., Bhattacharyya, A., Zhang, S.-C., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.02.001 · Cited by 122 · see citing works
Aziz, N. M., Guedj, F., Pennings, J. L. A., Olmos-Serrano, J. L., Siegel, A., Haydar, T. F., & Bianchi, D. W. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.031013 · Cited by 118 · see citing works
Wu, S., Xu, R., Duan, B., & Jiang, P. (2017) · Journal of Materials Chemistry B · doi:10.1039/c7tb00721c · Cited by 111 · see citing works
Global DNA Hypermethylation in Down Syndrome Placenta
Jin, S., Lee, Y. K., Lim, Y. C., Zheng, Z., Lin, X. M., Ng, D. P. Y., Holbrook, J. D., Law, H. Y., Kwek, K. Y. C., Yeo, G. S. H., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003515 · Cited by 99 · see citing works
Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of down Syndrome.
Goodliffe, J. W., Olmos-Serrano, J. L., Aziz, N. M., Pennings, J. L. A., Guedj, F., Bianchi, D. W., & Haydar, T. F. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.2513-15.2016 · Cited by 65 · see citing works
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
Neurodevelopment in Down syndrome: Concordance in humans and models
Klein, J. A., & Haydar, T. F. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.941855 · Cited by 47 · see citing works
“During the same time period (17– 21 weeks gestation) fewer neurons were found in the hippocampus (Guidi et al., 2008), cerebellum (Guidi et al.”
BackgroundShaw, P. R., Klein, J. A., Aziz, N. M., & Haydar, T. F. (2020) · Disease Models & Mechanisms · doi:10.1242/dmm.046243 · Cited by 45 · see citing works
Tramutola, A., Pupo, G., Di Domenico, F., Barone, E., Arena, A., Lanzillotta, C., Broekaart, D., Blarzino, C., Head, E., Butterfield, D. A., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151105 · Cited by 40 · 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
Laan, L., Klar, J., Sobol, M., Hoeber, J., Shahsavani, M., Kele, M., Fatima, A., Zakaria, M., Annerén, G., Falk, A., et al. (2020) · Clinical Epigenetics · doi:10.1186/s13148-019-0803-1 · Cited by 33 · 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
“…that fewer NPCs are produced before the transition to neurogenesis, which ultimately sets the stage for the production of fewer neurons 11,40,42–44, Second, it has been hypothesized that there is a premature transition from the neurogenic to the gliogenic stages, expanding the window of…”
InfluentialComprehensive volumetric phenotyping of the neonatal brain in Down syndrome
Fukami-Gartner, A., Baburamani, A. A., Dimitrova, R., Patkee, P. A., Ojinaga-Alfageme, O., Bonthrone, A. F., Cromb, D., Uus, A. U., Counsell, S. J., Hajnal, J. V., et al. (2023) · Cerebral Cortex · doi:10.1093/cercor/bhad171 · Cited by 24 · see citing works
Rethinking 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
Biphasic cell cycle defect causes impaired neurogenesis in down syndrome
Sharma, V., Nehra, S., Do, L. H., Ghosh, A., Deshpande, A. J., & Singhal, N. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.1007519 · Cited by 14 · see citing works
Prutton, K. M., Marentette, J. O., Leifheit, B. A., Esquer, H., LaBarbera, D. V., Anderson, C. C., Maclean, K. N., & Roede, J. R. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.04.015 · Cited by 13 · see citing works
Hawley, L. E., Stringer, M., Deal, A. J., Folz, A., Goodlett, C. R., & Roper, R. J. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106359 · Cited by 10 · see citing works
“…atypical cell cycle regulation, and abnormal cellular differentiation are hypothesized to contribute to the developmental deficits in brain structures in individuals with DS (Contestabile et al., 2007; Con-testabile et al., 2017; Guidi et al., 2008; Pinter et al., 2001; Stagni et al., 2018).”
Ishihara, K. (2021) · Genes · doi:10.3390/genes12101598 · Cited by 8 · see citing works
Postnatal Cytoarchitecture and neurochemical hippocampal dysfunction in Down Syndrome
Moreno, D. G., Utagawa, E. C., Arva, N. C., Schafernak, K. T., Mufson, E. J., & Perez, S. E. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10153414 · Cited by 7 · see citing works
- Authors
- Guidi, S., Bonasoni, P., Ceccarelli, C., Santini, D., Gualtieri, F., Ciani, E., & Bartesaghi, R.
- Affiliations
- University of Bologna (IT)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- ORCID
- Venue
- Brain Pathology
- Publisher
- Wiley
- Published
- 2008-01-03
- Volume
- 18
- Issue
- 2
- Pages
- 180-197
- ISSN
- 1015-6305 (ISSN-L)
- 1750-3639
- PMC
- PMC8095525
- OpenAlex
- W2102979724
- Cited by
- 276
- References
- 5
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 21 · 2023: 16 · 2022: 19 · 2021: 13 · 2020: 16 · 2019: 21 · 2018: 14 · 2017: 18 · 2016: 10 · 2015: 18 · 2014: 11 · 2013: 20 · 2012: 15
- FWCI
- 3.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- 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
- Keywords
- Down syndrome, neurogenesis, neuronal cell death, apoptosis, hippocampus, dentate gyrus, parahippocampal gyrus, fetal brain development, neuron number, cell proliferation, Ki-67
- MeSH terms
- Body Weight, Cell Count, Cell Differentiation, Down Syndrome, Female, Fetus, Glial Fibrillary Acidic Protein, Hippocampus, Humans, Infant, Male, Neurons, Phosphopyruvate Hydratase, Case-Control Studies, Cell Death, Ki-67 Antigen, Cell Proliferation, Caspase 3
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
