How the dosage of a Down syndrome candidate gene affects neural circuitry and behaviour (2016-2019)

People with Down syndrome harbour three copies of chromosome 21 and this results in brain wiring defects. How overexpression of genes on chromosome 21 leads to neurodevelopmental abnormalities is unknown. Here, we hypothesise that a gene called DSCAM, located within a region of chromosome 21 that is critical for Down syndrome, contributes to the brain defects and learning deficits observed in Down syndrome individuals. We will test this hypothesis in the fruit fly by studying the fly homologue of DSCAM, Dscam2. Our previous work demonstrated that Dscam2 plays a crucial role in wiring the brain. This cell-surface protein can bind to itself when expressed on opposing membranes, resulting in either adhesion or repulsion. We propose that the decision to adhere or repel other Dscam2 expressing cells is dependent on the amount of protein expressed on the two cell membranes. Cells with less protein mediate adhesion, whereas cells with more Dscam2 on their surface recruit signal transduction pathways that lead to repulsion. Thus, overexpression of Dscam2 (or DSCAM) would convert a subset of adhesive interactions into repulsion and disrupt the wiring of those neural circuits. We have built a strain of flies that is trisomic for Dscam2 and we will test this repulsive threshold model in vivo by analysing phenotypes in neurons that normally adhere to one another. In the second half of this study, we will investigate whether increasing the dosage of Dscam2 leads to learning deficits. Using a well established olfactory learning paradigm, we will determine whether too much or too little Dscam2 interferes with the fly¿¿¿s ability to learn. This project will provide novel insight into how overexpression of a Down syndrome candidate gene can lead to neuronal wiring and behavioural defects.