Insulin-like growth factor I (IGF-I) and its receptor are expressed in functionally related areas of the rat brain such as the inferior olive and the cerebellar cortex. A marked decrease of IGF-I levels in cerebellum is found when inferior olive neurons are lesioned. In addition, Purkinje cells in the cerebellar cortex depend on this growth factor to survive and differentiate in vitro. Thus, we consider it possible that IGF-I forms part of a putative trophic circuitry encompassing the inferior olive and the cerebellar cortex and possibly other functionally connected areas. To test this hypothesis we have studied whether IGF-I may be taken up, transported, and released from the inferior olive to the cerebellum. We have found that 12'I-IGF-I is taken up by inferior olive neurons in a receptor-mediated process and orthogradely transported to the cerebellum. Thus, radioactivity found in the cerebellar lobe contralateral to the injection site in the inferior olive was immunoprecipitated by an anti-IGF-I antibody, co-eluted with 12'I-IGF-I in an HPLC column, and co-migrated with '2sII-IGF-I in an SDS-urea polyacrylamide gel electrophoresis. Time-course studies indicated that orthograde axonal transport is relatively rapid since 30 min after the injection, radiolabeled IGF-I was already detected in the contralateral cerebellum. Furthermore, transport of IGF-I from the inferior olive is specific since when '2'I-neurotensin was injected in the inferior olive or when '251-IGF-I was injected in the pontine nucleus, no radiactivity was found in the contralateral cerebellum. In addition, no specific transport of I2'I-IGF-I was found in climbing fiber-deafferented rats or when excess unlabeled IGF-I was co-injected with I-IGF-I. We next studied whether IGF-I is released by inferior olive neurons. We found that the release of IGF-I from cerebellar slices of normal rats was significantly greater in response to depolarizing stimuli than that from slices obtained of climbing fiberdeafferented animals. Indeed, in vitro release of IGF-I in response to KCl or veratridine was almost completely abolished in the latter. These data suggest 125 that IGF-I is taken up by inferior olive neurons through IGF-I receptors and transported to the cer- ebellum through their axons without any major modification. Moreover, the release of IGF-I from the cerebellum after depolarization depends on the presence of climbing fiber afferents. Altogether these results indicate that the olivo-cerebellar pathway is able to take up, orthogradely transport, and reiease IGF-I. Since a similar process has been described in the visual system for basic fibroblast growth factor (bFGF), we propose that IGF-I, bFGF, and possibly other growth factors may constitute afferent trophic signals involved in plastic mechanisms within specific neural circuitries.