Neurotrophin-3 controls proliferation of granular precursors as well as survival of mature granule neurons in the developing rat cerebellum

Levels of neurotrophin-3 markedly decrease in the rat cerebellum after the first 10 days of life, suggesting an importance during early development. T o further examine the effect of neurotrophin-3 on the developing cerebellum , we injected a monoclonal antibody against neurotrophin-3 into the lateral ventricle of 7.5-day-old rats. The resultant depletion of neurotrophin-3 c aused a significant decrease in cerebellar wet weights noted at 7 and 23 da ys thereafter. Other changes noted 48 h after injection of monoclonal antib odies against neurotrophin-3 included reduced incorporation of bromodeoxyur idine into granule neurons in the external germinal layer, an elevated dens ity of atrophic neurons that had just migrated under the Purkinje cell laye r, and an increased number of apoptotic neurons in the internal granule cel l layer. These changes were limited to the central lobe. The concentration of neurotrophin-3 protein in the posterior region, including the central lo be, was about four- and threefold higher than that in the anterior region o f the cerebellum of 9.5- and 30-day-old rats, respectively. Immunocytochemi cal examination showed higher amounts of neurotrophin-3 protein in the cent ral lobe than in the anterior lobe. Our results provide evidence that neuro trophin-3 regulates the proliferation of granule precursors and supports th e survival of mature granule neurons in restricted lobules, suggesting an i nvolvement in limited regions at a specific stage in development of the rat cerebellum.