Motoneuron output regulated by ionic channels: a modeling study of motoneuron frequency-current relationships during fictive locomotion.

Cat lumbar motoneurons display changes in membrane properties during fictive locomotion. These changes include reduction of input resistance and afterhyperpolarization, hyperpolarization of voltage threshold, and voltage-dependent excitation of the motoneurons. The state-dependent alteration of membrane properties leads to dramatic changes in frequency-current (F-I) relationship. The mechanism underlying these changes remains unknown. Using a motoneuron model combined with electrophysiological data, we investigated the channel mechanisms underlying the regulation of motoneuronal excitability and motor output. Simulation results showed that upregulation of transient sodium, persistent sodium, or Cav 1.3 calcium conductances or downregulation of calcium-activated potassium or KCNQ/Kv 7 potassium conductances could increase motoneuronal excitability and motor output through hyperpolarizing (left shifting) the F-I relationships or increasing the F-I slopes, whereas downregulation of input resistance or upregulation of potassium-mediated leak conductance produced the opposite effects. The excitatory phase of locomotor drive potentials (LDPs) also substantially hyperpolarized the F-I relationships and increased the F-I slopes, whereas the inhibitory phase of the LDPs had opposite effects to a similar extent. The simulation results also showed that none of the individual channel modulations could produce all the changes in the F-I relationships. The effects of modulation of Cav 1.3 and KCNQ/Kv 7 on F-I relationships were supported by slice experiments with the Cav 1.3 agonist Bay K8644 and the KCNQ/Kv 7 antagonist XE-991. The conclusion is that the varying changes in F-I relationships during fictive locomotion could be regulated by multichannel modulations. This study provides insight into the ionic basis for control of motor output in walking. NEW & NOTEWORTHY Mammalian spinal motoneurons have their excitability adapted to facilitate recruitment and firing during locomotion. Cat lumbar motoneurons display dramatic changes in membrane properties during fictive locomotion. These changes lead to a varying alteration of frequency-current relationship. The mechanisms underlying the changes remain unknown. In particular, little is known about the ionic basis for regulation of motoneuronal excitability and thus control of the motor output for walking by the spinal motor system.