A Polarized Histamine-GABA Core-Rim Architecture within Synaptic Vesicles

Abstract Neuroscience traditionally assumes that amino acid transmitters occupy clear synaptic vesicles, whereas monoamines reside in dense-core vesicles. Using a glutaraldehyde-NaBH4; epitope-engineering platform enabling ultrastructural detection of small amines, we identify a polarized histamine-GABA vesicular organization within conventional GABAergic vesicles. Quantitative electron microscopy demonstrates histamine condensed into a dense intraluminal core, while complementary GABA immunolabeling supports the localization of GABA toward the vesicle periphery, consistent with a membrane-proximal rim. This conserved architecture across central, autonomic, and endocrine GABAergic systems provides a structural framework for temporally differentiated inhibitory signaling, challenges the clear-versus-dense-core vesicle paradigm, and establishes a unified principle for dual-transmitter architecture.