Excitatory amino acids, growth factors, and calcium: a teeter-totter model for neural plasticity and degeneration.
This paper presents and examines the hypothesis that excitatory amino acids (EAAs) and growth factors (GFs) exert opposing actions on neuronal cytoarchitecture by influencing cellular Ca2+ homeostasis. This hypothesis is supported by experiments with cultured hippocampal pyramidal neurons in which EAAs induced dendritic regression and cell death, whereas fibroblast GF (FGF) promoted neurite outgrowth and cell survival. FGF protected against glutamate-induced neuronal degeneration by raising the threshold for the actions of this EAA. Pharmacological studies, and direct monitoring of intracellular Ca2+ levels, demonstrated that a sustained rise in intracellular Ca2+ levels was largely responsible for the degenerative actions of glutamate. FGF attenuated the Ca2+ response to glutamate. Experiments with glutamate, Ca2+ ionophore A23187, and Na(+)-deficient culture medium provided evidence that FGF can enhance Na(+)-dependent Ca2+ extrusion. These data suggest a model in which cell survival and neurite outgrowth in hippocampal neurons is regulated by the opposing actions of EAAs and GFs acting through the Ca2+ second messenger system. In this "teeter-totter" model the relative levels of input from EAAs and GFs determine whether a neuron lives or dies, and whether its outgrowth is in a progressive or regressive state. Interactions of EAAs and GFs may play important roles in: developmental events such as neurite outgrowth, synaptogenesis, and natural cell death; maintenance and plasticity of neural circuitry in the mature nervous system; and maladaptive neurodegeneration that occurs in aging and disorders such as Alzheimer's disease.
Mattson
M P
MP
Sanders-Brown Research Center on Aging, University of Kentucky Medical Center, Lexington 40536-0230.
D000596:Amino Acids / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000502:physiology*; D009420:Nervous System / Q000254:growth & development; D009424:Nervous System Physiological Phenomena; D009473:Neuronal Plasticity / Q000502:physiology*
D000596:Amino Acids; D006133:Growth Substances; D002118:Calcium