AUTOCRINE BDNF SECRETION ENHANCES THE SURVIVAL AND SEROTONERGIC DIFFERENTIATION OF RAPHE NEURONAL PRECURSOR CELLS GRAFTED INTO THE ADULT-RAT CNS

RN46A cells are a temperature-sensitive neuronal cell line derived fro m the E13 rat raphe nucleus. RN46A cells grafted into the adult rat hi ppocampus and cerebral cortex do not survive beyond 2 weeks. Brain-der ived neurotrophic factor (BDNF) regulates the in vitro survival and se rotonergic phenotype of RN46A cells, and we hypothesized that expressi on of BDNF in RN46A cells would potentiate their survival and serotoni n (5HT) expression in vivo. The gene encoding rat BDNF was transfected into RN46A cells and the clonal 46A-B14 cell line isolated. 46A-B14 c ells synthesize and secrete biologically active BDNF in vitro and synt hesize 5HT following partial membrane depolarization. Two weeks follow ing 46A-B14 cell. transplantation into the adult rat cortex and hippoc ampus, there is a threefold increase in survival of 46A-B14 cells comp ared to RN46A cells transfected with the vector alone. The grafted 46A -B14 cells immunohistochemically stain for BDNF and 5HT, while RN46A c ells transfected with vector only are negative for both BDNF and 5HT, In addition, 46A-B14 cells attain more morphologically complex phenoty pes, indicating enhanced neuronal differentiation. Autocrine secretion of BDNF by RN46A cells thus potentiates survival and can be used to d eliver both BDNF and 5HT in vivo. (C) 1996 Academic Press, Inc.