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 rhythmi c burst pattern underlying locomotion when it is driven via synaptic g lutamate receptors. Lower rates of activity can be evoked by activatio n of N-methyl-D-aspartate (NMDA) receptors, whereas a rapid activity c an only be induced by non-NMDA receptors lpha-amino-3-hydroxy-5-methyl -4-isoxazolepropionic acid (AMPA)]. The reticulospinal and sensory inp uts are known to act via both NMDA and non-NMDA receptors, but it is u nclear how these inputs can provide an appropriate control of the loco motor rate. We have examined the effects of different types of excitat ory synaptic input to neurons of the locomotor network with the use of a computer-simulated electrical neuron model, with Na+, K+, Ca2+-depe ndent K+ channels, and with inherent oscillatory properties linked to the NMDA conductance. Synapses were modeled as a modulated ionic condu ctance in the membrane of the postsynaptic cell comprising a voltage-d ependent 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-typ e synapses, a continuous range of firing frequencies could be evoked i n the postsynaptic cell, by altering the firing rate of the presynapti c 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 oscill atory burst activity could be evoked. The rate of the oscillations was , however, little affected by the presynaptic firing rate. When a driv e 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 smal ler 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 synapse s. 4. A small rhythm-generating neuronal network, comprising six cells connected as the principal interneurons of the lamprey spinal locomot or network, was used to test the role of a tonic NMDA and non-NMDA rec eptor activation to drive the network and produce bursting. Although N MDA activation could only produce relatively slow bursting and non-NMD A activation mainly produced rapid bursting, a continuous range of bur st rates could be obtained by altering the relative balance between th e two types of conductance. However, higher rates of network bursting could not be produced if the strength of the inhibitory network synaps es was set too high. 5. When the network was driven by mixed synapses, a similar relation between conductance type and burst rate was observ ed. Adding ascending synaptic feedback from the locomotor network to t he drive neurons caused a rhythmic modulation of the latter and stabil ized the locomotor pattern. The stabilizing effect of such a feedback circuit was evident only when the synapses driving the' network did no t contain large NMDA components. 6. A movement-related feedback of the locomotor network was simulated by connecting phasically active ''mec hanosensitive'' inhibitory and excitatory neurons to the network inter neurons. When the excitatory synapses utilized non-NMDA conductances, the resting network bursting could be effectively entrained both towar d higher and lower burst rates. If NMDA synapses were used instead, th e entrainment became less effective. 7. The simulation results suggest that the synaptic control systems for locomotion modulates the segmen tal locomotor network both by providing patterned input signals and by controlling the balance between the NMDA and the kainate/AMPA recepto r-mediated synaptic input. The latter appear more efficient in providi ng 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 n on-NMDA conductances thus appears to be necessary in the living animal . This can be achieved by a selective recruitment of input neurons act ing at different postsynaptic conductance types, and/or by a different iated short-term plasticity, which for instance may cause a depression of synapses with large NMDA conductances when the presynaptic neuron fires at high rates.