Strategies for Understanding Novel Candidate Gene Functions in Down Syndrome Neural Circuit Development

The development and function of the human brain require precise interactions among cells, genes, and proteins. Brain cells compose a complex network of circuits with billions of neurons, each having thousands of synapses. Impairment of cellular connectivity by genetic mutations is responsible for conditions like intellectual disability. Down syndrome (DS), caused by triplication of some or all parts of chromosome 21, is the most common genetic cause of intellectual disability. The exact reasons for occurrence and factors leading to DS are unclear. The precise cellular and molecular mechanisms underlying impaired development remain elusive. Our focus is on identifying mechanisms related to the neuroscience aspects of DS. We aim to examine the individual and synergistic roles of the gene “coxsackievirus and adenovirus receptor” (CXADR), which is triplicated on human chromosome 21. We use a combination of mouse and human in vitro models to uncover the contribution of CXADR to the DS pathology, with the goal of better understanding DS, identifying molecular targets, and developing new diagnostics and treatments. Our central hypothesis is that triplication of this gene significantly changes brain development in DS, leading to intellectual disability. As a first step, we have two specific aims: (1) to measure and correlate the spatial-temporal expression of CXADR in a mouse model for DS and (2) in stem cell-derived human neurons from four different individuals with DS. Our lab at the University of Notre Dame has excellent expertise in working with mice and induced pluripotent stem cells. After initiation of this new research project, future work aims to functionally assess the contribution of CXADR by genetically correcting their CXADR triplication in patient-derived human neurons.