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Journal of Neuroscience, Vol 9, 3728-3740, Copyright © 1989 by Society for Neuroscience
Fibroblast growth factor and glutamate: opposing roles in the generation and degeneration of hippocampal neuroarchitecture
MP Mattson, M Murrain, PB Guthrie and SB Kater
Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Lexington 40536.
Neuritic regression and cell death (neurodegeneration) are common features
of both normal nervous system development and neurodegenerative disorders.
Growth factors and excitatory amino acid neurotransmitters have been
suggested independently to play roles in neurodegenerative processes. The
present study investigated the combined effects of fibroblast growth factor
(FGF) and glutamate on the development and degeneration of cultured
hippocampal neurons. Consistent with previous data, we found that FGF, but
not NGF, promoted neuronal survival and dendritic outgrowth. In contrast, a
low level of glutamate (50 microM) caused a reduction in dendritic
outgrowth, and high levels (100 microM-1 mM) reduced neuronal survival in a
dose- dependent manner. When cultures were maintained in the presence of
FGF, there was a striking reduction in neuronal death normally caused by
100- 500 microM glutamate. FGF raised the threshold for glutamate
neurotoxicity. FGF also antagonized the outgrowth-inhibiting actions of
glutamate. Measurements of intracellular calcium levels with fura-2
demonstrated a direct relationship between glutamate-induced rises in
intracellular calcium and neurodegeneration. FGF reduced the glutamate-
induced increases in intracellular calcium levels. However, when cultures
were pretreated with the RNA synthesis inhibitor actinomycin D or with the
protein synthesis inhibitor cycloheximide, FGF did not prevent
glutamate-induced increases in intracellular calcium or neurodegeneration.
Taken together, these results suggest that (1) interactions between growth
factors and neurotransmitters may be important in brain development; (2)
imbalances in these systems may lead to neurodegeneration; and (3) cellular
calcium-regulating systems may be a common focus of growth factor and
neurotransmitter actions.
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