Neuronal plasticity in the developing and mature nervous system is mediated in part by the availability of target-derived trophic molecules. The events involved in regulating the expression of these trophic factors are not well understood. However, recent studies provide evidence that neuronal activity involving activation of glutamate receptors may regulate mRNA expression of a family of trophic molecules, the neurotrophins, in the central nervous system (CNS). This chapter describes findings that further delineate neuronal mechanisms influencing mRNA levels of nerve growth factor (NGF) in the CNS. We report that a single intraventricular injection of N-methyl-D-aspartate (NMDA) induces mRNA expression of NGF mRNA in a time- and dose-dependent fashion. This increase is observed exclusively in the granule cells of the DG, occurs in the absence of detectable excitotoxicity and seizure activity, and can be blocked with an NMDA-specific antagonist. We also report that high-frequency stimulation of the perforant path, a putative glutamatergic afferent to the hippocampal formation, also increases mRNA expression of this neurotrophin in the DG. As observed following NMDA injections, the effects of perforant path stimulation can be blocked by pretreatment with an NMDA receptor antagonist, but not a non-NMDA antagonist. These studies provide evidence that physiological events mediated through glutamatergic transmission can regulate expression of target-derived neurotrophins. The altered expression of this neurotrophic factor may ultimately influence the plasticity of NGF-responsive neuronal populations, including the basal forebrain cholinergic neurons.
Dr. J. Springer would like to thank Dr. R. L. Isaacson for his continued guidance and inspiration, and B. Hogan for his technical assistance. This work supported by Public Health Service grants AGO8969 and NS30502 to JES.
Ayer-LeLievre C., Olson L., Ebendal T., Seiger A., & Persson H. ( 1988). "Expression of the ß-nerve growth factor gene in hippocampal neurons". Science, 240,1339-1341.
Bliss T. V. P., & Lomo T. ( 1973). Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path. Journal of Psychology, 232,331-356.
Choi D. W. ( 1988). "Glutamate neurotoxicity and diseases of the nervous system". Neuron, 1, 623-634.