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Journal of Neuroscience, Vol 12, 4793-4799, Copyright © 1992 by Society for Neuroscience
Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes
F Zafra, D Lindholm, E Castren, J Hartikka and H Thoenen
Department of Neurochemistry, Max Planck Institute for Psychiatry, Planegg-Martinsried, Germany.
Brain-derived neurotrophic factor (BDNF) and NGF are both expressed by
neurons in the hippocampus. In previous studies, it has been demonstrated
that both BDNF and NGF mRNA levels are regulated by neuronal activity.
Upregulation is predominantly regulated by the glutamate (NMDA and non-NMDA
receptors); downregulation, predominantly by the GABA system (Zafra et al.,
1990, 1991). In neuronal cultures of the rat hippocampus, potassium
depolarization and kainic acid-mediated increases in BDNF and NGF mRNA were
eliminated in a dose-dependent manner by the calcium channel blocker
nifedipine. Conversely, calcium ionophores (Bay-K8644 and ionomycin)
augmented BDNF and NGF mRNA levels by a calmodulin-mediated mechanism. In
view of the fact that many potential modulators (conventional transmitters
and neuropeptides) of neuronal and astrocytic BDNF and NGF mRNA synthesis
may act via the adenylate cyclase system, we studied the effect of
forskolin, an activator of adenylate cyclase. Indeed, forskolin enhanced
the effects of calcium ionophores and kainic acid on BDNF and NGF mRNA
levels. Cytokines, such as interleukin-1 and transforming growth
factor-beta 1, which have previously been shown to increase NGF mRNA
markedly in astrocytes, were without effect on neuronal BDNF and NGF mRNA
levels. In contrast to neuronal cultures, where the regulation of BDNF and
NGF mRNA was generally very similar, the regulation in astrocytes was
distinctly different. All the cytokines that produce a marked increase in
NGF mRNA were without effect on astrocyte BDNF mRNA levels, which under
basic conditions were below the detection limit. However, norepinephrine
produced a marked elevation of BDNF mRNA in astrocytes, an effect that was
further enhanced by glutamate receptor agonists.(ABSTRACT TRUNCATED AT 250
WORDS)
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