A matter of space and time: Emerging roles of disease-associated proteins in neural development

Recent genetic studies of neurodevelopmental disorders point to synaptic proteins and ion channels as key contributors to disease pathogenesis. Although many of these proteins, such as the L-type calcium channel Ca_v1.2 or the postsynaptic scaffolding protein SHANK3, have well-studied functions in mature neurons, new evidence indicates that they may subserve novel, distinct roles in immature cells as the nervous system is assembled in prenatal development. Emerging tools and technologies, including single-cell sequencing and human cellular models of disease, are illuminating differential isoform utilization, spatiotemporal expression, and subcellular localization of ion channels and synaptic proteins in the developing brain compared with the adult, providing new insights into the regulation of developmental processes. We propose that it is essential to consider the temporally distinct and cell-specific roles of these proteins during development and maturity in our framework for understanding neuropsychiatric disorders.