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Following a Demyelinating Lesion, the Metabotropic Agonist ACPD Increases Myelin Proteins by Regulating the Production of Astrocyte-derived BDNF

by
Clifton G. Fulmer
B.S., The College of New Jersey - 2006

Thesis Advisor: Cheryl Dreyfus, Ph.D.
Graduate Program in Neuroscience

CABM, Room 010
Piscataway

Thursday, May 30, 2013
11:00 a.m.


Abstract

Previous studies indicated that BDNF impacts development and remyelination of oligodendrocyte (OLG) lineage cells. Thus, BDNF promotes DNA synthesis in progenitors and differentiation of cultured OLGs (Vanít Veer 2009, Du 2006) and BDNF +/- mice exhibit deficits in NG2+ progenitors and decreased myelin proteins (VonDran 2010). After cuprizone treatment, BDNF +/- mice demonstrate blunted increases in NG2 and decreases in MBP, MAG and PLP. Moreover, BDNF injection into a cuprizone lesioned corpus callosum increases MBP. To increase endogenous levels of BDNF following demyelination, the current work examines in vivo effects of the metabotropic glutamate receptor (mGluR) agonist ACPD, known to upregulate BDNF and promote its release from glial cells in vitro (Bagayogo 2009, Jean 2008). ACPD (0.5uM) injected into the corpus callosum of mice fed control or cuprizone (0.2%) feed for 4 weeks exhibit increased BDNF, MBP and MAG compared to mice injected with vehicle. This effect was completely blocked by coadministration of TrkB-fc, indicating that the ACPD effect is mediated by BDNF. Immunocytochemical analysis used to evaluate Group I and II metabotropic glutamate receptors as well as BDNF revealed that GFAP+ astrocytes present in the cuprizone lesioned corpus callosum express both the Group I receptors and BDNF. To determine the role of these astrocytes in ACPD effects, GFAP-CreER2-flBDNF mice that delete BDNF specifically in astrocytes upon tamoxifen injection were injected (2X, 5days) and fed cuprizone or control feed for 4 weeks. When these mice that had the deletion were injected with ACPD or control saline, ACPD-elicited increases in BDNF, MBP and MAG were eliminated. On the other hand, ACPD increases did occur in mice where astrocyte-derived BDNF is maintained. These studies suggest that ACPD increases the production of BDNF by astrocytes in the cuprizone lesioned corpus callosum, which in turn provides trophic support to OLG lineage cells.


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