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Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome

Nature Neuroscience volume 13, pages 927–934 (2010)Cite this article

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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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Figure 1: Preferential overproduction of a subset of interneurons in Ts65Dn neocortex.
Figure 2: Overproduction of a subset of interneurons in Ts65Dn hippocampus.
Figure 3: Increased gene expression and proliferation in the MGE of the Ts65Dn ventral telencephalon.
Figure 4: Normalization of Olig genes rescues the neurogenesis phenotype in Ts65Dn Olig1+/−; Olig2+/− (TsOlig1/2+/−) MGE.
Figure 5: Gene dosage reduction rescues inhibitory neuron phenotype in embryonic Ts65Dn Olig1+/−; Olig2+/− telencephalon.
Figure 6: Normal number of inhibitory neurons in postnatal Ts65Dn Olig1+/−; Olig2+/− neocortex.
Figure 7: Reduction in Olig1 and Olig2 gene dosage rescues the electrophysiological phenotype in Ts65Dn CA1 pyramidal cells.

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References

  1. Epstein, C.J. Developmental genetics. Experientia 42, 1117–1128 (1986).

    Article  CAS  PubMed  Google Scholar 

  2. Korenberg, J.R. et al. Down syndrome: toward a molecular definition of the phenotype. Am. J. Med. Genet. Suppl. 7, 91–97 (1990).

    CAS  PubMed  Google Scholar 

  3. Golden, J.A. & Hyman, B. Development of the superior temporal neocortex is anomalous in trisomy 21. J. Neuropathol. Exp. Neurol. 53, 513–520 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Schmidt-Sidor, B., Wisniewski, K.E., Shepard, T.H. & Sersen, E.A. Brain growth in Down syndrome subjects 15 to 22 weeks of gestational age and birth to 60 months. Clin. Neuropathol. 9, 181–190 (1990).

    CAS  PubMed  Google Scholar 

  5. Weitzdoerfer, R., Dierssen, M., Fountoulakis, M. & Lubec, G. Fetal life in Down syndrome starts with normal neuronal density but impaired dendritic spines and synaptosomal structure. J. Neural Transm. Suppl. 61, 59–70 (2001).

    Google Scholar 

  6. Baxter, L.L., Moran, T.H., Richtsmeier, J.T., Troncoso, J. & Reeves, R.H. Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. Hum. Mol. Genet. 9, 195–202 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Chakrabarti, L., Galdzicki, Z. & Haydar, T.F. Defects in embryonic neurogenesis and initial synapse formation in the forebrain of the Ts65Dn mouse model of Down syndrome. J. Neurosci. 27, 11483–11495 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lorenzi, H.A. & Reeves, R.H. Hippocampal hypocellularity in the Ts65Dn mouse originates early in development. Brain Res. 1104, 153–159 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Belichenko, P.V. et al. Excitatory-inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of Down syndrome. J. Comp. Neurol. 512, 453–466 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Belichenko, P.V. et al. Synaptic structural abnormalities in the Ts65Dn mouse model of Down syndrome. J. Comp. Neurol. 480, 281–298 (2004).

    Article  PubMed  Google Scholar 

  11. Kleschevnikov, A.M. et al. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J. Neurosci. 24, 8153–8160 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Siarey, R.J., Stoll, J., Rapoport, S.I. & Galdzicki, Z. Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down syndrome. Neuropharmacology 36, 1549–1554 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Costa, A.C., Walsh, K. & Davisson, M.T. Motor dysfunction in a mouse model for Down syndrome. Physiol. Behav. 68, 211–220 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Hyde, L.A., Frisone, D.F. & Crnic, L.S. Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function. Behav. Brain Res. 118, 53–60 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Reeves, R.H. et al. A mouse model for Down syndrome exhibits learning and behavior deficits. Nat. Genet. 11, 177–184 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Kurt, M.A., Davies, D.C., Kidd, M., Dierssen, M. & Florez, J. Synaptic deficit in the temporal cortex of partial trisomy 16 (Ts65Dn) mice. Brain Res. 858, 191–197 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Perez-Cremades, D. et al. Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down's syndrome. J. Neural Transm. 117, 445–455 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Costa, A.C. & Grybko, M.J. Deficits in hippocampal CA1 LTP induced by TBS, but not HFS, in the Ts65Dn mouse: a model of Down syndrome. Neurosci. Lett. 382, 317–322 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Fernandez, F. et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat. Neurosci. 10, 411–413 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Haydar, T.F. Advanced microscopic imaging methods to investigate cortical development and the etiology of mental retardation. Ment. Retard. Dev. Disabil. Res. Rev. 11, 303–316 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Miller, M.W. Cogeneration of retrogradely labeled corticocortical projection and GABA-immunoreactive local circuit neurons in cerebral cortex. Brain Res. 355, 187–192 (1985).

    Article  CAS  PubMed  Google Scholar 

  22. Valcanis, H. & Tan, S.S. Layer specification of transplanted interneurons in developing mouse neocortex. J. Neurosci. 23, 5113–5122 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. DeFelipe, J. Neocortical neuronal diversity: chemical heterogeneity revealed by colocalization studies of classic neurotransmitters, neuropeptides, calcium-binding proteins and cell surface molecules. Cereb. Cortex 3, 273–289 (1993).

    Article  CAS  PubMed  Google Scholar 

  24. Kawaguchi, Y. & Kubota, Y. GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cereb. Cortex 7, 476–486 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Markram, H. et al. Interneurons of the neocortical inhibitory system. Nat. Rev. Neurosci. 5, 793–807 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Wonders, C.P. & Anderson, S.A. The origin and specification of cortical interneurons. Nat. Rev. Neurosci. 7, 687–696 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Hobert, O. & Westphal, H. Functions of LIM-homeobox genes. Trends Genet. 16, 75–83 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Liodis, P. et al. Lhx6 activity is required for the normal migration and specification of cortical interneuron subtypes. J. Neurosci. 27, 3078–3089 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shirasaki, R. & Pfaff, S.L. Transcriptional codes and the control of neuronal identity. Annu. Rev. Neurosci. 25, 251–281 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Eisenstat, D.D. et al. DLX-1, DLX-2, and DLX-5 expression define distinct stages of basal forebrain differentiation. J. Comp. Neurol. 414, 217–237 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Grigoriou, M., Tucker, A.S., Sharpe, P.T. & Pachnis, V. Expression and regulation of Lhx6 and Lhx7, a novel subfamily of LIM homeodomain encoding genes, suggests a role in mammalian head development. Development 125, 2063–2074 (1998).

    CAS  PubMed  Google Scholar 

  32. Porteus, M.H., Bulfone, A., Ciaranello, R.D. & Rubenstein, J.L. Isolation and characterization of a novel cDNA clone encoding a homeodomain that is developmentally regulated in the ventral forebrain. Neuron 7, 221–229 (1991).

    Article  CAS  PubMed  Google Scholar 

  33. Sussel, L., Marin, O., Kimura, S. & Rubenstein, J.L. Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Development 126, 3359–3370 (1999).

    CAS  PubMed  Google Scholar 

  34. Alifragis, P., Liapi, A. & Parnavelas, J.G. Lhx6 regulates the migration of cortical interneurons from the ventral telencephalon, but does not specify their GABA phenotype. J. Neurosci. 24, 5643–5648 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lu, Q.R. et al. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109, 75–86 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Takebayashi, H. et al. Dynamic expression of basic helix-loop-helix Olig family members: implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3. Mech. Dev. 99, 143–148 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Zhou, Q. & Anderson, D.J. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109, 61–73 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Bertrand, N., Castro, D.S. & Guillemot, F. Proneural genes and the specification of neural cell types. Nat. Rev. Neurosci. 3, 517–530 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Ma, Q. Transcriptional regulation of neuronal phenotype in mammals. J. Physiol. (Lond.) 575, 379–387 (2006).

    Article  CAS  Google Scholar 

  40. Miyoshi, G., Butt, S.J., Takebayashi, H. & Fishell, G. Physiologically distinct temporal cohorts of cortical interneurons arise from telencephalic Olig2-expressing precursors. J. Neurosci. 27, 7786–7798 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kahlem, P. et al. Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of Down syndrome. Genome Res. 14, 1258–1267 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Contestabile, A. et al. Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with down syndrome and in Ts65Dn mice. Hippocampus 17, 665–678 (2007).

    Article  PubMed  Google Scholar 

  43. Segal, D.J. & McCoy, E.E. Studies on Down's syndrome in tissue culture. I. Growth rates and protein contents of fibroblast cultures. J. Cell. Physiol. 83, 85–90 (1974).

    Article  CAS  PubMed  Google Scholar 

  44. Clark, S., Schwalbe, J., Stasko, M.R., Yarowsky, P.J. & Costa, A.C. Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome. Exp. Neurol. 200, 256–261 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Freund, T.F. & Buzsaki, G. Interneurons of the hippocampus. Hippocampus 6, 347–470 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. Dierssen, M. et al. Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: effects of environmental enrichment. Cereb. Cortex 13, 758–764 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Gibson, J.R., Bartley, A.F., Hays, S.A. & Huber, K.M. Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. J. Neurophysiol. 100, 2615–2626 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Polleux, F. & Lauder, J.M. Toward a developmental neurobiology of autism. Ment. Retard. Dev. Disabil. Res. Rev. 10, 303–317 (2004).

    Article  PubMed  Google Scholar 

  49. Cortez, M.A. et al. Infantile spasms and Down syndrome: a new animal model. Pediatr. Res. 65, 499–503 (2009).

    Article  PubMed  Google Scholar 

  50. Harashima, C. et al. Abnormal expression of the G protein–activated inwardly rectifying potassium channel 2 (GIRK2) in hippocampus, frontal cortex and substantia nigra of Ts65Dn mouse: a model of Down syndrome. J. Comp. Neurol. 494, 815–833 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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  1. Tarik F Haydar

    Present address: Present address: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.,

Authors and Affiliations

  1. Center for Neuroscience Research, Children's National Medical Center, Washington, DC, USA

    Lina Chakrabarti, Rosalind S E Carney & Tarik F Haydar

  2. Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

    Tyler K Best, Nathan P Cramer & Zygmunt Galdzicki

  3. Developmental Synaptic Plasticity Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA

    John T R Isaac

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Contributions

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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Correspondence to Tarik F Haydar.

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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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