The locus ceruleus responds to signaling molecules obtained from the CSF by transfer through tanycytes

Neurons can access signaling molecules through two principal pathways: synaptic transmission ("wiring transmission") and nonsynaptic transmission ("volume transmission"). Wiring transmission is usually considered the far more important mode of neuronal signaling. Using embryonic chick locus ceruleus (LoC) as a model, we quantified and compared routes of delivery of the neurotrophin nerve growth factor (NGF), either through a multisynaptic axonal pathway or via the CSF. We now show that the axonal pathway from the eye to the LoC involves axo-axonic transfer of NGF with receptor switching (p75 to trkA) in the optic tectum. In addition to the axonal pathway, the LoC of chick embryos has privileged access to the CSF through a specialized glial/ependymal cell type, the tanycyte. The avian LoC internalizes from the CSF in a highly specific fashion both NGF and the hormone urotensin (corticotropin-releasing factor family ligand). Quantitative autoradiography at the ultrastructural level shows that tanycytes transcytose and deliver NGF to LoC neurons via synaptoid contacts. The LoC-associated tanycytes express both p75 and trkA receptors. The NGF extracted by tanycytes from the CSF has physiological effects on LoC neurons, as evidenced by significantly altered nuclear diameters in both gain-of-function and loss-of-function experiments. Quantification of NGF extraction shows that, compared with multisynaptic axonal routes of NGF trafficking to LoC, the tanycyte route is significantly more effective. We conclude that some clinically important neuronal populations such as the LoC can use a highly efficient "back door" interface to the CSF and can receive signals via this tanycyte-controlled pathway.