Reversing Abnormal Neural Development by Inhibiting OLIG2 in Down Syndrome Human iPSC Brain Organoids and Neuronal Mouse Chimeras

Down syndrome (DS), caused by triplication of human chromosome 21 (HSA21), is the most common genetic origin of intellectual disability. Despite the limited success of current pharmacological interventions, little has been achieved to reverse the abnormal brain developmental in DS. Here, using human induced pluripotent stem cell (hiPSC)-based brain organoid and in vivo human neuronal chimeric mouse brain models, we demonstrate that the HSA21 genes OLIG1 and OLIG2 exhibit distinct temporal expression patterns during neuronal differentiation. The population of OLIG2-expressing ventral forebrain neural progenitors is overabundant in DS, which results in excessive production of calretinin- and somatostatin-expressing GABAergic interneurons and causes impaired recognition memory in DS chimeric mice. Furthermore, we find that overexpression of OLIG2 in DS alters the expression of GABAergic neuron lineage-determining transcription factors such as DLX1 and LHX8. We further show that OLIG2 can directly bind to promoter regions of DLX1 and LHX8 to increase their expression, leading to lineage specification of interneurons. Importantly, knockdown of OLIG2 largely reverses the abnormal global gene expression profile of early stage DS neural progenitors, reduces inhibitory neuronal population in DS organoids and chimeric mouse brains, as well as improves behavioral performance of DS chimeric mice. Therefore, OLIG2 potentially is a target for developing prenatal personalized therapeutics for intellectual disability in subjects with DS