Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome

Summary

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 (DS). Here we demonstrate a direct link between gene triplication and defects in neuron production during embryonic development. These neurogenesis defects lead 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 triplicated in DS and Ts65Dn, are over-expressed in the Ts65Dn forebrain. To test the hypothesis that Olig triplication is causative for 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 demonstrate a mechanistic relationship between triplicated genes and these brain abnormalities in the Ts65Dn mouse.