Brain-derived neurotrophic factor influences olfactory bulb granule cell development: Evidence for p75 receptor mediated mechanisms.

摘要

Olfactory bulb (OB) granule cells (GCs) are distinctive neurons in the brain in that they lack axons, develop spines with both afferent and efferent functions and continue to migrate and incorporate into the bulb throughout postnatal development and adulthood. Brain-derived neurotrophic factor (BDNF) has been implicated in the migration and survival of newly generated GCs in neonatal and adult OB. However, while BDNF's role in dendritic growth and morphology has been explored in other brain regions, it has not been examined for the GC. The purpose of this project was to explore the potential role of BDNF in GC development. An in vitro model system was developed in which granule-like cells and dendritic protrusions could be differentiated using a combination of protein and morphologic markers (Chapter 1). Pharmacologic manipulations were applied to the culture system to evaluate granule-like cells for BDNF-induced dendritic phenotypes and determine the responsible receptors (Chapter 2). Lastly, immunofluorescent localization of BDNF and its receptors, trkB and p75, was pursued in intact OB to see if the proteins implicated in vitro are appropriately expressed in situ (Chapter 3).; The data reveal that a readily distinguishable granule-like cell type is present in OB dissociated cultures. These anaxonic cells exhibit pedunculated dendritic protrusions that resemble dendritic spines in their morphology and F-actin distribution but lack more specific spine markers. These structures likely represent spine precursors, termed protospines. BDNF exposure produced a dose-dependent increase in the number of protospines present on granule-like cells. This effect was blocked by antibody against p75 receptor, but not by an inhibitor of receptor tyrosine kinases, suggesting that p75 receptor activation may mediate BDNF effects on GCs. The complementary expression pattern of BDNF and p75 receptor in postnatal OB, and the transient expression of p75 receptor on cells of the rostral migratory stream are consistent with the idea that BDNF may impact granule cell development via a p75 receptor-mediated mechanism.