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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Acknowledgements
We wish to thank V. Gallo, J. Corbin, and members of Corbin and Haydar laboratories for discussions and critical reading of the manuscript. This work was supported by a Dana Foundation Neuro-Immuno Imaging grant (T.F.H.), RO1 HD05780 (T.F.H. and Z.G.), the National Down Syndrome Society (L.C.), the Jerome Lejeune Foundation (Z.G.), Uniformed Services University of the Health Sciences (Z.G.) and a gift from Robin and Rob Wilder. Imaging was supported by the Intellectual and Developmental Disabilities Research Center (P30 HD40677).
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L.C. performed the experiments, analyzed the data, wrote the manuscript and generated the figures. T.K.B., N.P.C. (both contributed equally), J.T.R.I. and Z.G. performed the electrophysiology experiments, analyzed data and revealed the physiological phenotype. R.S.E.C. generated the RNA probes. T.F.H. generated the hypothesis, designed experiments, analyzed data and wrote the manuscript.
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Chakrabarti, L., Best, T., Cramer, N. et al. Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome. Nat Neurosci 13, 927–934 (2010). https://doi.org/10.1038/nn.2600
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DOI: https://doi.org/10.1038/nn.2600
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