Electron microscopic immunolabeling of transporters and receptors identifies transmitter-specific functional sites envisioned in Cajal's neuron.

Neuronal arborizations that were so elegantly demonstrated in the early drawings of Santiago Ramón y Cajal can now be viewed by high resolution electron microscopic immunocytochemical localization of vesicular and plasmalemmal neurotransmitter transporters and receptors. The subcellular distribution of these proteins confers both chemical selectivity and functional specificity to the dendritic and axonal arborizations described by Cajal. This is illustrated by central dopaminergic and cholinergic neurons. Dopamine terminals in the striatum and ventral pallidum, as well as dendrites of midbrain dopaminergic neurons in the ventral tegmental area and substantia nigra express the plasmalemmal dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2). In forebrain regions, the dopamine D2 receptor (D2R) autoreceptor is localized to dopamine terminals, but also is targeted to pre- and postsynaptic neuronal profiles at a distance from the dopamine terminals. In somata and dendrites of the midbrain dopaminergic neurons, D2R labeling is expressed in most dendrites that contain VMAT2 storage vesicles, as well as in both excitatory and inhibitory afferents. Together, these observations indicate that dopamine is stored in and released from vesicles in both dendrities and axons, and may activate either local or more distant receptors through volume transmission. By analogy, the vesicular acetylcholine transporter (VachT) is similarly localized to the membranes of axon terminals and tubulovesicles in dendrities in the mesopontine tegmental cholinergic nuclei, suggesting that there also may be release of acetylcholine from both dendrities and axons. These results identify chemically selective functional sites for neuronal signaling envisioned by Cajal and redefined by modern technology.