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

Nitric oxide (^.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 ^.NO-selective microssensors inserted into the diffusional field of ^.NO in acute hippocampal slices, we describe the ^.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 ^.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 ^.NO signals, reaching undetectable levels for distances > 400 μm, supporting the notion of a wide diffusional spread of endogenously generated ^.NO in the hippocampus. Neither a picoinjection nor a continuous perfusion of NMDA resulted in high steady-state ^.NO levels; rather all signals were transient, suggesting that cells are able to efficiently respond to high ^.NO concentrations (typically 200-400 nM) bringing it to very low nM levels; the claimed high micromolar ^.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 ^.NO activity and/or regulation among the hippocampal subregions. These findings may be relevant for the understanding of the role of ^.NO in physiologic mechanisms in the hippocampus and the differential sensitivity of the hippocampal subregions to NMDA receptor-dependent neurodegeneration.