Concentration Dynamics of Nitric Oxide in Rat Hippocampal Slices

Abstract

Nitric oxide () 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 -selective microssensors inserted into the diffusional field of in acute hippocampal slices, we describe the 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 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 signals, reaching undetectable levels for distances >400 μm, supporting the notion of a wide diffusional spread of endogenously generated in the hippocampus. Neither a picoinjection nor a continuous perfusion of NMDA resulted in high steady-state levels; rather all signals were transient, suggesting that cells are able to efficiently respond to high concentrations (typically 200-400 nM) bringing it to very low nM levels; the claimed high micromolar 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 activity and/or regulation among the hippocampal subregions. These findings may be relevant for the understanding of the role of in physiologic mechanisms in the hippocampus and the differential sensitivity of the hippocampal subregions to NMDA receptor-dependent neurodegeneration.