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. The parent award was funded to build models based on human induced pluripotent stem cells (iPSCs), to interrogate how T21 disrupts developmental processes in DS. The iPSC model will be validated by integrating cellular changes and molecular signatures of single cells in vitro with DS prenatal cortex. The parent award relies on maintenance, differentiation and analysis of iPSC derived neurons in vitro for two of the three Aims. This supplement requests funding for cell culture related equipment that is required to carry out Aims 2 and 3 of the parent award. Funding is requested to replace two cell culture incubators for maintenance of iPSCs and differentiated neurons in Aim 2 and 3. Funding is also requested for an additional electrophysiological rig for analysis of iPSC derived neurons in Aim 3. The parent award included minimal equipment funding and these costs were unforeseen when the application was awarded.

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.