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

Down syndrome results from the triplication of human chromosome 21 and is the leading cause of intellectual disability. Down syndrome cell adhesion molecule (DSCAM) is located on human chromosome 21 and is overproduced in Down syndrome. DSCAM is a homophilic cell adhesion molecule, a receptor for netrin-1, and plays a critical role in neural wiring during brain development. Using a Dscam gain-of-function mouse model and human induced pluripotent stem cell-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 Down syndrome. Analysis of morphological parameters revealed impaired neuronal development and loss of netrin-1-mediated axon guidance in mouse hippocampal pyramidal neurons overexpressing DSCAM. DSCAM overexpression also reduces interhemispheric connectivity in vivo. Furthermore, we find that DSCAM overexpression leads to impaired hippocampal-dependent learning and reduced anxiety in adult mice. Down syndrome human induced pluripotent stem cell-derived excitatory pyramidal neurons exhibit a similar phenotype: impaired morphological development and loss of netrin-1-mediated axon guidance. Remarkably, normalization of DSCAM in Down syndrome human induced pluripotent stem cell-derived neurons rescues many of these neuronal phenotypes, including reduced axon length and deficits in axon guidance. This study presents the first comprehensive cellular, molecular, and behavioural evidence that DSCAM is a significant contributor to multiple Down syndrome phenotypes, providing insight into a pathway for treatment. In summary, 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 Down syndrome.