Restoring DSCAM expression rescues neuronal morphology and axon guidance deficits in Down syndrome

Down syndrome (DS) results from the triplication of human chromosome 21 (HSA21) and is the leading cause of intellectual disability. Down syndrome cell adhesion molecule (DSCAM) is located on HSA21 and is overproduced in DS. DSCAM is a receptor for netrin-1 and important for neural wiring in the developing brain. Using a Dscam gain-of-function mouse model and human induced pluripotent stem cell (hiPSC)-derived cortical neurons, in combination with cellular, molecular, and behavioral approaches, this study aims to understand how DSCAM triplication and its subsequent excessive production contribute to changes in neural development and intellectual disability in DS. Analysis of morphological parameters revealed impaired neuronal development and loss of netrin-1-mediated axon guidance in mouse hippocampal pyramidal neurons overexpressing DSCAM. Furthermore, DSCAM overexpression reduces interhemispheric connectivity in vivo, and hippocampal- dependent learning in adult mice. DS hiPSC-derived excitatory pyramidal neurons exhibit a similar phenotype: impaired morphological development and loss of netrin-1-mediated axon guidance. Remarkably, normalization of DSCAM in DS hiPSC-derived neurons rescues many of these neuronal phenotypes, including reduced axon length and deficits in axon guidance. These results suggest that DSCAM plays an essential role in the development of neurons and neuronal networks, and its overproduction contributes to intellectual disability in DS.