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Cited by 258Down syndrome and intellectual disability researchNeurogenesis and neuroplasticity mechanismsGenetics and Neurodevelopmental Disorders

Olig1 and Olig2 triplication causes developmental brain defects in down syndrome.

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Chakrabarti, Lina, Best, Tyler K, Cramer, Nathan P, Carney, Rosalind S E, Isaac, John T R, Galdzicki, Zygmunt, Haydar, Tarik F·2010·Nature Neuroscience
DOI 10.1038/nn.2600PMC PMC3249618
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Abstract

Over-inhibition is thought to be one of the underlying causes of the cognitive deficits in Ts65Dn mice, the most widely used model of Down syndrome. We found a direct link between gene triplication and defects in neuron production during embryonic development. These neurogenesis defects led to an imbalance between excitatory and inhibitory neurons and to increased inhibitory drive in the Ts65Dn forebrain. We discovered that Olig1 and Olig2, two genes that are triplicated in Down syndrome and in Ts65Dn mice, were overexpressed in the Ts65Dn forebrain. To test the hypothesis that Olig triplication causes the neurological phenotype, we used a genetic approach to normalize the dosage of these two genes and thereby rescued the inhibitory neuron phenotype in the Ts65Dn brain. These data identify seminal alterations during brain development and suggest a mechanistic relationship between triplicated genes and these brain abnormalities in the Ts65Dn mouse.

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  • In young Ts65Dn mice (postnatal day 8-30), there is a significant increase in the number of parvalbumin and somatostatin positive interneurons in the sensorimotor cortex and hippocampus, with no difference in calretinin positive neurons.

    “In young Ts65Dn from postnatal day 8–30, a significant increase in the number of parvalbumin and somatostatin positive interneurons has been measured in the sensorimotor cortex and the hippocampus, though no difference in calretinin positive neurons was identified, contrary to previous data in humans (Chakrabarti et al., 2010).”

    From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Chakrabarti et al., 2010

    The Results section, “Neuronal allocation is impaired in Ts65Dn forebrain” (page not available), reports increased parvalbumin- and somatostatin-positive neurons in the neocortex at P8, P15 and P30, and no significant change in cortical calretinin-positive cells. The Methods specify that cortical measurements were made at the sensorimotor cortex. The hippocampal finding is limited to CA1 at P15; the cited results do not establish the same pattern across P8–P30 or report no change in hippocampal calretinin-positive cells. (LLM, conf=0.87)

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  • Contrary to the existing human data, these proliferation changes in Ts65Dn appear to be region specific as an increase in number of actively proliferating cells was observed in the embryonic medial ganglionic eminence, the site of interneuron production.

    “Contrary to the existing human data, these proliferation changes appear to be region specific as an increase in number of actively proliferating cells was observed in the embryonic medial ganglionic eminence, the site of interneuron production (Chakrabarti et al., 2010; Aziz et al., 2018).”

    From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Chakrabarti et al., 2010

  • Striking conservation was found in the ratio of ExN:InN (2.17:1) and the ratio of MGE:CGE InNs (1.4:1) in both control and Ts21 samples.

    “Whereas Ts21 mouse models have identified alterations in the balance of ExN and InN (43-45), we found striking conservation in the ratio of ExN:InN (2.17:1) and the ratio of MGE:CGE InNs (1.4:1) in both control and Ts21 samples (Fig. 4B).”

    From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [44]

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References 52 · Cited by 258

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Authors
Chakrabarti, L., Best, T. K., Cramer, N. P., Carney, R. S. E., Isaac, J. T. R., Galdzicki, Z., & Haydar, T. F.
Affiliations
  • Children's National (US)
  • Uniformed Services University of the Health Sciences (US)
  • National Institute of Neurological Disorders and Stroke (US)
  • Boston University (US)
Corresponding author
Haydar, Tarik F
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2010-07-18
Volume
13
Issue
8
Pages
927-934
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.2600
PMC
PMC3249618
OpenAlex
W2032903160
Cited by
258
References
52
Citations by year
2026: 8 · 2025: 11 · 2024: 9 · 2023: 10 · 2022: 22 · 2021: 15 · 2020: 11 · 2019: 16 · 2018: 10 · 2017: 14 · 2016: 12 · 2015: 13 · 2014: 11 · 2013: 19 · 2012: 16
FWCI
30.54
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Dana Foundation
  • National Institute of Neurological Disorders and Stroke (R01NS076503)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD40677, R01 HD05780, R01HD057580, P30HD040677)
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, Olig1, Olig2, gene triplication, Ts65Dn mouse model, neurogenesis, inhibitory neurons, excitatory-inhibitory imbalance, forebrain development, cognitive impairment, transcription factors
MeSH terms
Oligodendrocyte Transcription Factor 2, Animals, Brain, Brain Diseases, Disease Models, Animal, Down Syndrome, Immunohistochemistry, Nerve Tissue Proteins, Neurons, Blotting, Western, In Situ Hybridization, Patch-Clamp Techniques, Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, Embryonic Development, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Inhibitory Postsynaptic Potentials

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