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Melissa Wood VonDran
Thesis Advisor: Cheryl F. Dreyfus, PhD
Graduate Program: Neuroscience & Cell Biology
Wednesday, February 10, 2010
Previous work in culture has shown that basal forebrain (BF) oligodendrocyte lineage cells (OLCs) respond to BDNF by increasing DNA synthesis and differentiation. These effects are mediated by the trkB, tyrosine kinase receptor. I hypothesize that BDNF impacts OLCs in vivo as it does in culture during development and after a demyelinating lesion. Western blot and immunocytochemical analyses were used to define effects on oligodendrocyte (OLG) traits in wildtype and BDNF +/- animals.
Initial studies indicated that OLCs in the BF and corpus callosum express the trkB receptor and are capable of responding to BDNF. In the BF, BDNF +/- mice exhibited reduced numbers of NG2+ cells at embryonic day 17, postnatal day 1 (P1), P14, and adult. BDNF +/+ and +/- mice exhibited similar numbers of CC1+ post-mitotic OLGs. However, BDNF +/- mice exhibited deficits in myelin proteins, myelin basic protein (MBP), myelin-associated glycoprotein (MAG), and proteolipid protein (PLP). BDNF, then, impacts the proliferating population of OLGs as well as differentiation in the BF in vivo as it does in culture. In contrast, BDNF +/- mice did not exhibit deficits in OLCs in the corpus callosum, illustrating the heterogeneity of neurotrophin response in the brain.
To investigate roles BDNF may play in the repair of a demyelinating lesion, the cuprizone model was used. BDNF protein levels were reduced after 3 to 6 weeks of cuprizone, suggesting that the lesion elicits a reduction in BDNF synthesis. To analyze effects of a further reduction of BDNF on OLCs following cuprizone, BDNF +/- mice were evaluated. These mice exhibited a blunted increase in the NG2 response at 4 and 5 weeks of cuprizone. BDNF +/- mice exhibited similar losses of CC1+ cells as wildtype mice, indicating that BDNF does not affect mature OLG numbers. However, BDNF +/- mice exhibited decreased levels of MBP during demyelination and remyelination processes. These data indicate that BDNF may play a role following a demyelinating lesion by regulating numbers of progenitors and the ability of differentiating cells to express MBP. BDNF, then, may be useful as a therapeutic agent for demyelinating diseases, such as Multiple Sclerosis.