Concentration Dynamics of Nitric Oxide in Rat Hippocampal Subregions Evoked by Stimulation of the NMDA Glutamate Receptor

Nitric oxide ($^\bullet NO$) production in response to stimulation of the NMDA glutamate receptor is implicated not only in the synaptic plasticity in hippocampus but may also participate in excitotoxic cell death. Using$^\bullet NO-selective$microssensors inserted into the diffusional field of$^\bullet NO$in acute hippocampal slices, we describe the$^\bullet NO$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$^\bullet NO$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$^\bullet NO$signals, reaching undetectable levels for distances$>400 \mu m$, supporting the notion of a wide diffusional spread of endogenously generated$^\bullet NO$in the hippocampus. Neither a picoinjection nor a continuous perfusion of NMDA resulted in high steady-state$^\bullet NO$levels; rather all signals were transient, suggesting that cells are able to efficiently respond to high$^\bullet NO$concentrations (typically 200-400 nM) bringing it to very low nM levels; the claimed high micromolar$^\bullet NO$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$^\bullet NO$activity and/or regulation among the hippocampal subregions. These findings may be relevant for the understanding of the role of$^\bullet NO$in physiologic mechanisms in the hippocampus and the differential sensitivity of the hippocampal subregions to NMDA receptor-dependent neurodegeneration.