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Next Article 
The Journal of Neuroscience, May 1, 1999, 19(9):3277-3286
Brain-Derived Neurotrophic Factor Mediates the
Anti-Apoptotic Effect of NMDA in Cerebellar Granule Neurons: Signal
Transduction Cascades and Site of Ethanol Action
Sanjiv V.
Bhave,
Lucy
Ghoda, and
Paula L.
Hoffman
Department of Pharmacology, University of Colorado Health Sciences
Center, Denver, Colorado 80262
Cerebellar granule neurons cultured in medium containing a
physiological concentration of KCl (5 mM) undergo
apoptosis. The cells can be rescued by the in vitro
addition of NMDA. The protective effect of NMDA is thought to reflect
the in vivo innervation of developing cerebellar granule
neurons by glutamatergic afferents. In the current work, we
investigated the mechanism of the anti-apoptotic (protective) effect of
NMDA. NMDA treatment reduced caspase-3-like activity in cerebellar
granule neurons, and the time course and concentration dependence of
the protective effect of NMDA mirrored the ability of NMDA to induce
brain-derived neurotrophic factor (BDNF) expression. Furthermore, a Trk
receptor antagonist, K252a, as well as a blocking antibody to BDNF,
attenuated the protective effects of both NMDA and BDNF. These results
suggest that NMDA-induced BDNF expression mediates the anti-apoptotic
effect of NMDA. The protective effects of NMDA and BDNF were reduced by
inhibitors of the phosphatidylinositol 3'-OH kinase (PI 3-kinase)
signal transduction cascade (wortmannin and LY29004) but not by a MAP kinase kinase (MEK) inhibitor (PD98059) or a protein kinase A inhibitor
(Rp-cAMPS). BDNF increased phosphorylation of Akt, a target of PI
3-kinase, and NMDA also induced Akt phosphorylation, but only after an
exposure that was long enough to induce BDNF expression. Furthermore,
ethanol, which interferes with NMDA receptor function, inhibited the
NMDA-induced increase in BDNF levels but did not block the protective
effect of BDNF. These findings further support the role of
BDNF in the anti-apoptotic effect of NMDA in cerebellar granule neurons
and suggest that the NMDA-BDNF interaction may play a key role in
in vivo cerebellar granule neuron development, as well
as in the deleterious effects of ethanol on the developing cerebellum.
Key words:
cerebellar granule neurons; apoptosis; NMDA; BDNF; PI
3-kinase; MAP kinase; ethanol
Copyright © 1999 Society for Neuroscience 0270-6474/99/1993277-10$05.00/0
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