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Metabotropic receptors regulate the release of BDNF from basal forebrain astrocytes

by
Ying Y. Jean
B.S., 2000
Purdue University

Thesis Advisor: Cheryl F. Dreyfus, Ph.D.
Graduate Program in Neuroscience and Cell Biology

CABM 010

Monday, October 13, 2008
1:00 pm


Abstract

Our laboratory has demonstrated that basal forebrain (BF) astrocytes express BDNF mRNA (Wu et al., 2004). The present study evaluated effects of astrocyte-derived BDNF on proximate neurons and regulation of BDNF expression in and release from BF astrocytes. Conditioned medium (CM) collected over a 4-day period from BF astrocytes increased the number of acetylcholinesterase (AChE) positive cholinergic neurons and the activity of choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, in BF neuronal cultures. Effects of CM were reduced by an anti-BDNF neutralizing antibody (Promega), suggesting the involvement of BDNF. To define events regulating astrocyte expression of BDNF, cultures were treated for 4 hours with glutamate (100 uM). Glutamate elicited significant increases in BDNF mRNA and protein that were reproduced by the group I and II metabotropic agonist t-ACPD (10 uM), and blocked by antagonist (+)-MCPG (1mM) or the intracellular Ca2+ chelator BAPTA-AM (50 uM), suggesting the mediation by metabotropic receptors and dependence on Ca2+. To define events regulating BDNF release, astrocytes were treated for 10 minutes with glutamate or t-ACPD. Both agents increased the release of BDNF. Moreover, release was blocked by (+)-MCPG, BAPTA-AM, the general PLC inhibitor U73122 (10 uM), and the IP3 inhibitor 2-APB (150 uM), implicating the PLC pathway. These results suggest that glutamate, through the mediation of metabotropic receptors, regulates BDNF expression in and release from astrocytes, and that astrocyte-derived BDNF may affect the survival and function of BF cholinergic neurons.


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