Local mechanisms of phase-dependent postsynaptic modifications of NMDA-induced oscillations in the abducens motoneurons: a simulation study

1. In vivo experiments have shown that extracellular microelectrophoretic application of N-methyl-D-aspartate (NMDA) induced oscillatory plateau potentials with bursts of action potentials in rat abducens motoneurons. The period of these slow NMDA oscillations could be altered by single trigeminal non-NMDA excitatory input delivered at low frequency during the NMDA oscillations. 2. A resetting of the oscillations was observed depending on the phase of slow oscillatory cycle during which the trigeminal excitation occurred. 3. We investigated local mechanisms responsible for the phase-dependent modifications of NMDA oscillations, including contributions of voltage and concentration transients, in the mathematical model of the isopotential membrane compartment equipped with voltage-gated Na+, K+, and Ca2+ channels, with Ca2+-dependent K+ channels, and with ligand-gated NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels. The faithful model was constructed with the use of models described earlier, which were modified by increasing time constants of kinetic variables of all voltage-gated conductances and by including coupled dynamics of voltages and ion concentrations. The changes in ion concentrations were produced near the membrane by transmembrane currents and removal mechanisms (pumps, diffusion). 4. This work focuses on local arrangement of voltage- and ligand-gated conductances and on local ion concentration changes in two separate pools: the postsynaptic pool of AMPA receptors and the extrasynaptic pool. In terms of the electrotonic and diffusional length constants, these pools were electrotonically close but diffusionally remote. 5. It was found that the effect of resetting can be produced by a local interaction between plateau and spike-generating conductances and glutamate receptors. 6. In vivo phase-dependent interactions between NMDA oscillations and AMPA synaptic input were reproduced by the local model only when changes in intracellular sodium and extracellular potassium concentrations were taken into account and the mechanisms of ion removal from postsynaptic pools had slower kinetics than the fast pump system operating in the extracellular pool. 7. Postsynaptic changes in ion concentrations of Na+ and K+ in intra- and extracellular layers near the membrane shift of Nernst equilibrium potentials for these ions depending on the phase of activation of synaptic input. Thus Na+ and k+ components of all transmembrane currents involved in the pattern generation are differently affected by synaptic action during the oscillations. We conclude that slow postsynaptic changes in ion concentrations near the membrane play a key role in the resetting of the NMDA oscillations.