ORTHOGRADE TRANSPORT AND RELEASE OF INSULIN-LIKE GROWTH FACTOR-I FROMTHE INFERIOR OLIVE TO THE CEREBELLUM

Insulin-like growth factor I (IGF-I) and its receptor are expressed in functionally related areas of the rat brain such as the inferior oliv e and the cerebellar cortex. A marked decrease of IGF-I levels in cere bellum 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 t hat IGF-I forms part of a putative trophic circuitry encompassing the inferior olive and the cerebellar cortex and possibly other functional ly connected areas. To test this hypothesis we have studied whether IG F-I may be taken up, transported, and released from the inferior olive to the cerebellum. We have found that I-125-IGF-I is taken up by infe rior olive neurons in a receptor-mediated process and orthogradely tra nsported to the cerebellum. Thus, radioactivity found in the cerebella r lobe contralateral to the injection site in the inferior olive was i mmunoprecipitated by an anti-IGF-I antibody, co-eluted with I-125-IGF- I in an HPLC column, and co-migrated with I-125-IGF-I in an SDS-urea p olyacrylamide 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 contralater al cerebellum. Furthermore, transport of IGF-I from the inferior olive is specific since when I-125-neurotensin was injected in the inferior olive or when I-125-IGF-I was injected in the pontine nucleus, no rad iactivity was found in the contralateral cerebellum. In addition, no s pecific transport of I-125 IGF-I was found in climbing fiber-deafferen ted rats or when excess unlabeled IGF-I was co-injected with I-125-IGF -1. We next studied whether IGF-I is released by inferior olive neuron s. We found that the release of IGF-I from cerebellar slices of normal rats was significantly greater in response to depolarizing stimuli th an that from slices obtained of climbing fiber-deafferented animals. I ndeed, in vitro release of IGF-I in response to KCl or veratridine was almost completely abolished in the latter. These data suggest hat IGF -I is taken up by inferior olive neurons through IGF-I receptors and t ransported to the cerbellum through their axons without any major modi fication. Moreover, the release of IGF-I from the cerebellum after dep olarization depends on the presence of climbing fiber afferents. Altog ether these results indicate that the olivo-cerebellar pathway is able to take up, orthogradely transport, and release IGF-I. Since a simila r 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 pl astic mechanisms within specific neural circuitries. (C) 1993 Wiley-Li ss, Inc.