Original Article Brain-Derived Neurotrophic Factor Deficiency Restricts Proliferation of

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that through its neurotrophic tyrosine kinase, receptor, type 2 (TrkB) receptor, increases 5-bromo-2-deoxyuridine incorporation in oligo-dendrocyte progenitor cells (OPCs) in culture. Roles in vivo are less well understood; however, increases in numbers of OPCs are restricted in BDNFþ/ mice following cuprizone-elicited demyelination. Here, we investigate whether these blunted increases in OPCs are associated with changes in proliferation. BDNFþ/þ and BDNFþ/ mice were fed cuprizone-contain-ing or control feed. To assess effects on OPC numbers, platelet-derived growth factor receptor alpha (PDGFRa)þ or NG2þ cells were counted. To monitor DNA synthesis, 5-ethynyl-20-deoxyuridine (EdU) was injected intraperitoneally and coloca-lized with PDGFRaþ cells. Alternatively, proliferating cell nuclear antigen (PCNA) was colocalized with PDGFRa or NG2. Labeling indices were determined in the BDNFþ/þ and BDNFþ/ animals. After 4 or 5 weeks of control feed, BDNFþ/ mice exhibit similar numbers of OPCs compared with BDNFþ/þ animals. The labeling indices for EdU and PCNA also were not significantly different, suggesting that neither the DNA synthesis phase (S phase) nor the proliferative pool size was different between genotypes. In contrast, when mice were challenged by cuprizone for 4 or 5 weeks, increases in OPCs observed in BDNFþ/þ mice were reduced in the BDNFþ/ mice. This difference in elevations in cell number was accompanied by decreases in EdU labeling and PCNA labeling without changes in cell death, indicating a reduction in the DNA synthesis and the proliferative pool. Therefore, levels of BDNF influence the proliferation of OPCs resulting from a demyelinating lesion