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BDNF heightens the sensitivity of motor neurons to excitotoxic insults through activation of TrkBThe survival promoting and neuroprotective actions of brain-derived neurotrophic factor (BDNF) are well known but under certain circumstances this growth factor can also exacerbate excitotoxic insults to neurons. Prior exploration of the receptor through which BDNF exerts this action on motor neurons deflects attention away from p75. Here we investigated the possibility that BDNF acts through the receptor tyrosine kinase, TrkB, to confer on motor neurons sensitivity to excitotoxic challenge. We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody, and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons. Addition of a function blocking antibody to BDNF to mixed spinal cord neuron cultures is also neuroprotective indicating that endogenously produced BDNF participates in vulnerability to excitotoxicity. We next examined the intracellular signaling cascades that are engaged upon TrkB activation. Previously we found that inhibition of the phosphatidylinositide-3'-kinase (PI3'K) pathway blocks BDNF-induced excitotoxic sensitivity. Here we show that expression of a constitutively active catalytic subunit of PI3'K, p110, confers excitotoxic sensitivity (ES) upon motor neurons not incubated with BDNF. Parallel studies with purified motor neurons confirm that these events are likely to be occuring specifically within motor neurons. The abrogation of BDNF's capacity to accentuate excitotoxic insults may make it a more attractive neuroprotective agent.
Document ID
20040087813
Acquisition Source
Legacy CDMS
Document Type
Reprint (Version printed in journal)
Authors
Hu, Peter
(Yale University School of Medicine New Haven, Connecticut, United States)
Kalb, Robert G.
Walton, K. D.
Date Acquired
August 21, 2013
Publication Date
March 1, 2003
Publication Information
Publication: Journal of neurochemistry
Volume: 84
Issue: 6
ISSN: 0022-3042
Subject Category
Life Sciences (General)
Funding Number(s)
CONTRACT_GRANT: NS37874
CONTRACT_GRANT: NS29837
Distribution Limits
Public
Copyright
Other
Keywords
Non-NASA Center
NASA Discipline Neuroscience

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