A study published in Nature Neuroscience this week reports that normalizing the gene expression of two of the hundreds of affected genes in a mouse model of Down syndrome (DS) can be beneficial in combating some of the effects of the disease.
Animals generally have two copies of each gene ― one set inherited from each parent ― with the exception of sex chromosomes. In DS patients, however, there is an extra copy of chromosome 21 which results in severe learning disabilities and cognitive impairments. Despite the availability of several mouse models of DS that recapture some of the behavioral and neurodevelopment deficits of DS, finding the gene or set of genes directly responsible for DS has been elusive.
Tarik Haydar and colleagues show that reducing the expression of two of the affected genes ― Olig1 and Olig2 ― in a mouse model of DS can help correct the imbalance of brain activity in DS mice. Olig1 and Olig2 are essential during embryonic development, as these genes regulate the numbers of interneurons ― a type of neuron that controls the levels of inhibition in the brain. An imbalance between excitation and inhibition has been reported in DS patients. Although these results show promise, it remains unclear whether altering the gene dosage of Olig1 and Olig2 would be beneficial to correct the behavioral impairments seen in DS mouse models. It also remains to be seen whether the behavioral deficits associated with DS are normalized by lowering the level of Olig1 and Olig2.
Although it is difficult to directly link these results to the cognitive impairments or extrapolate to the disease condition in humans with DS, these findings could help identify some potential therapeutic targets for combating the initial development of DS.