COMPUTER-SIMULATIONS OF NMDA AND NON-NMDA RECEPTOR-MEDIATED SYNAPTIC DRIVE - SENSORY AND SUPRASPINAL MODULATION OF NEURONS AND SMALL NETWORKS

1. The segmental locomotor network in lamprey can generate the rhythmic burst pattern underlying locomotion when it is driven via synaptic glutamate receptors. Lower rates of activity can be evoked by activation of N-methyl-D-aspartate (NMDA) receptors, whereas a rapid activity can only be induced by non-NMDA receptors [kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)]. The reticulospinal and sensory inputs are known to act via both NMDA and non-NMDA receptors, but it is unclear how these inputs can provide an appropriate control of the locomotor rate. We have examined the effects of different types of excitatory synaptic input to neurons of the locomotor network with the use of a computer-simulated electrical neuron model, with Na+, K+, Ca2+-dependent K+ channels, and with inherent oscillatory properties linked to the NMDA conductance. Synapses were modeled as a modulated ionic conductance in the membrane of the postsynaptic cell comprising a voltage-dependent NMDA component (Na+, K+, Ca2+ conductances) of long duration, and/or a non-NMDA component (Na+, K+ conductance) of short duration. 2. By using two neurons to drive a postsynaptic cell with non-NMDA-type synapses, a continuous range of firing frequencies could be evoked in the postsynaptic cell, by altering the firing rate of the presynaptic cells. If a single presynaptic neuron was used, there was a tendency toward spike synchronization between the pre- and postsynaptic cells. 3. When a postsynaptic neuron was driven via NMDA synapses, an oscillatory burst activity could be evoked. The rate of the oscillations was, however, little affected by the presynaptic firing rate. When a drive neuron with mixed (NMDA and non-NMDA) synapses was used, the rate of the oscillations could be changed within a limited frequency range by altering the presynaptic firing rate. By adding another larger drive neuron, having a larger rheo-base current and mixed synapses with smaller relative NMDA components, the frequency range of the postsynaptic oscillations could be markedly increased. The frequency range depended on the parameters selected for each of the two types of mixed synapses. 4. A small rhythm-generating neuronal network, comprising six cells connected as the principal interneurons of the lamprey spinal locomotor network, was used to test the role of a tonic NMDA and non-NMDA receptor activation to drive the network and produce bursting. Although NMDA activation could only produce relatively slow bursting and non-NMDA activation mainly produced rapid bursting, a continuous range of burst rates could be obtained by altering the relative balance between the two types of conductance. However, higher rates of network bursting could not be produced if the strength of the inhibitory network synapses was set too high. 5. When the network was driven by mixed synapses, a similar relation between conductance type and burst rate was observed. Adding ascending synaptic feedback from the locomotor network to the drive neurons caused a rhythmic modulation of the latter and stabilized the locomotor pattern. The stabilizing effect of such a feedback circuit was evident only when the synapses driving the' network did not contain large NMDA components. 6. A movement-related feedback of the locomotor network was simulated by connecting phasically active ''mechanosensitive'' inhibitory and excitatory neurons to the network interneurons. When the excitatory synapses utilized non-NMDA conductances, the resting network bursting could be effectively entrained both toward higher and lower burst rates. If NMDA synapses were used instead, the entrainment became less effective. 7. The simulation results suggest that the synaptic control systems for locomotion modulates the segmental locomotor network both by providing patterned input signals and by controlling the balance between the NMDA and the kainate/AMPA receptor-mediated synaptic input. The latter appear more efficient in providing a direct phasic control of the burst pattern, whereas NMDA synapses mainly appear to act by stabilizing the rhythmic motor output, but it also limits the frequency range. A selective control of NMDA versus non-NMDA conductances thus appears to be necessary in the living animal. This can be achieved by a selective recruitment of input neurons acting at different postsynaptic conductance types, and/or by a differentiated short-term plasticity, which for instance may cause a depression of synapses with large NMDA conductances when the presynaptic neuron fires at high rates.