Tonically active NMDA receptors - a signalling mechanism critical for interneuronal excitability in the CA1 stratum radiatum

In contrast to tonic extrasynaptic gamma-aminobutyric acid (GABA) A receptor-mediated signalling, the physiological significance of tonic extrasynaptic N-methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated signalling remains uncertain. In this study, reversible open-channel blockers of NMDARs, memantine and phencyclidine (PCP) were used as tools to examine tonic NMDAR-mediated signalling in rat hippocampal slices. Memantine in concentrations up to 10 mu M had no effect on synaptically evoked NMDAR-mediated responses in pyramidal neurons or GABAergic interneurons. On the other hand, 10 mu M memantine reduced tonic NMDAR-mediated currents in GABAergic interneurons by approximately 50%. These tonic NMDAR-mediated currents in interneurons contributed significantly to the excitability of the interneurons as 10 mu M memantine reduced the disynaptic inhibitory postsynaptic current in pyramidal cells by about 50%. Moreover, 10 mu M memantine, but also PCP in concentrations <= 1 mu M, increased the magnitude of the population spike, likely because of disinhibition. The relatively higher impact of tonic NMDAR-mediated signalling in interneurons was at least partly explained by the expression of GluN2D-containing NMDARs, which was not observed in mature pyramidal cells. The current results are consistent with the idea that low doses of readily reversible NMDAR open-channel blockers preferentially inhibit tonically active extrasynaptic NMDARs, and they suggest that tonically active NMDARs contribute more prominently to the intrinsic excitation in GABAergic interneurons than in pyramidal cells. It is proposed that this specific difference between interneurons and pyramidal cells can explain the disinhibition caused by the Alzheimer's disease medication memantine.