ABSTRACT Down syndrome (DS, trisomy 21, T21), a complex multigene disorder and the most common genetic cause of intellectual disability. However, surprisingly little is known about the underlying mechanisms that lead to cognitive impairment in DS. There are fewer neurons in adult DS cortex and reduced neurogenesis and synaptogenesis have been implicated as features of DS development. Yet, what and how specific neurons and synaptic contacts are affected at which period of development and what molecular pathways underlie these defects that lead to intellectual disability remain unclear. We propose to build models based on human induced pluripotent stem cells (iPSCs), to interrogate how T21 disrupts developmental processes in DS. To ensure the validity of the stem cell based models, we will first establish a cellular, synaptic, and molecular atlas of the DS prenatal cortex. By integrating molecular signatures of single cells with the cellular changes both in vivo and in in vitro models, we will tease out the molecular pathways that are disrupted by T21 that account for the altered neural development. The results from these experiments will provide mechanistic understanding of intellectual disability in DS. More broadly, the results will address gaps in our understanding of human cortical neuron development and consequences of mistakes.

PROJECT NARRATIVE As the most common genetic developmental disorder that leads to intellectual disability, Down syndrome is a public health concern. The proposed research will better define the developmental defects that occur during formation of the human brain in Down syndrome. The results will provide insight into the biological bases of intellectual and developmental disabilities and could potentially lead to the design of therapeutic interventions.