Membrane excitability and cell-to-cell communication in the brain are tightly regulated by diverse ion channels and receptor proteins localized to distinct membrane compartments. Currently, a major technical barrier in cellular neuroscience is lack of reliable methods to label these membrane proteins and image their sub-cellular localization and dynamics. To overcome this challenge, we devised optical imaging strategies that enable systematic characterization of subcellular composition, relative abundances and trafficking dynamics of membrane proteins at nanometer scales in cultured neurons as well as in the brain. Using these methods, we revealed exquisite developmental regulation of subcellular distributions of voltage-gated sodium channel (VGSC) Nav1.2 and Nav1.6, settling a decade long debate regarding the molecular identity of sodium channels in dendrites. In addition, we discovered a previously uncharacterized trafficking pathway that targets Nav1.2 to unmyelinated fragments in the distal axon. Myelination counteracts this pathway, facilitating the installment of Nav1.6 as the dominant VGSC in the axon. Together, these imaging approaches unveiled compartment-specific trafficking mechanisms underpinning differential membrane distributions of VGSCs and open avenues to decipher how membrane protein localization and dynamics contribute to neural computation in the brain.
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