Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome

Abstract

Down syndrome is caused by the triplication of chromosome 21, which results in extra copies of hundreds of genes. Chakrabarti et al. used the Ts65Dn mouse model of Down syndrome to show that Olig1 and Olig2, two transcription factor genes that are triplicated in Down syndrome and in the Ts65Dn mouse, are involved in the manifestation of the inhibition/excitation imbalance phenotype. 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.