Concentration dynamics of nitric oxide in rat hippocampal subregions evoked by stimulation of the NMDA glutamate receptor

Nitric oxide ((NO)-N-center dot) production in response to stimulation of the NMIDA glutamate receptor is implicated not only in the synaptic plasticity in hippocampus but may also participate in excitotoxic cell death. Using (NO)-N-center dot-selective microssensors inserted into the diffusional field of (NO)-N-center dot in acute hippocampal slices, we describe the (NO)-N-center dot concentration dynamics evoked by NMDA receptor activation and report profound differences along the trisynaptic loop of the hippocampus. We measured the oxygen gradient across the slice thickness and conclude that (NO)-N-center dot measurements were performed at cell layers experiencing physiological oxygen tensions. Recordings performed at increasing distances from the point of NMDA receptor stimulation resulted in a progressive decrease of (NO)-N-center dot signals, reaching undetectable levels for distances > 400 mu m, supporting the notion of a wide diffusional spread of endogenously generated (NO)-N-center dot in the hippocampus. Neither a picoinjection nor a continuous perfusion of NMDA resulted in high steady-state (NO)-N-center dot levels; rather all signals were transient, suggesting that cells are able to efficiently respond to high (NO)-N-center dot concentrations (typically 200-400 nM) bringing it to very low nM levels; the claimed high micromolar (NO)-N-center dot range achieved by excessive stimulation of NMDA receptor may have to be reevaluated. The distinct responses to NMDA receptor stimulation along the trysynaptic loop suggest a differential (NO)-N-center dot activity and/or regulation among the hippocampal subregions. These findings may be relevant for the understanding of the role of (NO)-N-center dot in physiologic mechanisms in the hippocampus and the differential sensitivity of the hippocampal subregions to NMDA receptor-dependent neurodegeneration.