Disrupted Neurogenesis from Basal Intermediate Precursor Cells Alters the Postnatal Neocortex in the TcMAC21 Mouse model of Down Syndrome.

Abstract

Cognitive, social behavior, speech, and motor skills are known challenges for people with trisomy 21/Down syndrome (DS) but the precise mechanisms that lead to these impactful changes have not yet been described. Data from human and mouse model fetal brains indicate that alterations in prenatal neurogenesis might account for the neurological phenotypes that manifest after birth. Here, we evaluated key features of cortical neurogenesis in the humanized mouse model of DS (TcMAC21 of undetermined sex) to test whether and how the presence of the human HSA21q transchromosome impacts cortical development. Brain growth measurements throughout the second half of gestation and at several periods of postnatal development show overall that the TcMAC21 brain phenotype is less severe than in other DS mouse models that have less genetic similarity to humans with DS. However, despite the lack of gross changes in brain growth, we uncovered a significant temporally limited neurogenesis defect at mid-gestation that correlates with long-lasting effects on neuronal dispersion and neuronal function in the neocortex. Using Cre/Lox mediated genetic fate mapping we discovered a transient reduction in neocortical basal intermediate neural precursors (bIPCs) and that bIPC neuronal progeny are under-represented in the superficial layers of the neocortex. This change in neuronal production is associated with cortical activity changes after birth. Altogether, our data isolate the cell types associated with a very specific temporal change in cortical formation that, due to the high levels of excitability of bIPC-derived neurons, creates lasting effects on network activity and circuit development in trisomic brains.Significance Statement This study, using a mouse model of Down syndrome (DS) with high genetic relevance to human trisomy 21, suggests that a specific population of excitatory neurons in the cerebral cortex is perturbed during fetal brain development. Production of these neurons, from a group of embryonic progenitor cells called basal intermediate progenitor cells (bIPCs), is decreased in mid-gestation, and the neurons successfully produced from intermediate progenitor cells (IPCs) show altered positioning in the mature cerebral cortex of the DS mouse brain. This change in neurogenesis likely contributes to altered connectivity and electrical activity in the DS brain.