NERVE GROWTH-FACTOR RAPIDLY SUPPRESSES BASAL, NMDA-EVOKED, AND AMPA-EVOKED NITRIC-OXIDE SYNTHASE ACTIVITY IN RAT HIPPOCAMPUS IN-VIVO

In adult forebrain, nerve growth factor (NGF) influences neuronal main tenance and axon sprouting and is neuroprotective in several injury mo dels through mechanisms that are incompletely understood. Most NGF sig naling is thought to occur after internalization and retrograde transp ort of trkA receptor and be mediated through the nucleus. However, NGF expression in hippocampus is rapidly and sensitively regulated by syn aptic activity, suggesting that NGF exerts local effects more dynamica lly than possible through signaling requiring retrograde transport to distant afferent neurons. Interactions have been reported between NGF and nitric oxide (NO), Because NO affects both neural plasticity and d egeneration, and trk receptors can mediate signaling within minutes, w e hypothesized that NGF might rapidly modulate NO production. Using in vivo microdialysis we measured conversion of L-[C-14]arginine to L-[C -14]citrulline as an accurate reflection of NO synthase (NOS) activity in adult rat hippocampus. NGF significantly reduced NOS activity to 6 1% of basal levels within 20 min of onset of delivery and maintained N OS activity at less than 50% of baseline throughout 3 hr of delivery. This effect did not occur with control protein (cytochrome c) and was not mediated by an effect of NGF on glutamate levels. In addition, sim ultaneous delivery of NGF prevented significant increases in NOS activ ity triggered by the glutamate receptor agonists N-methyl-D-aspartate (NMDA) and lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AM PA), Rapid suppression by NGF of basal and glutamate-stimulated NOS ac tivity may regulate neuromodulatory functions of NO or protect neurons from NO toxicity and suggests a novel mechanism for rapidly mediating functions of NGF and other neurotrophins.