Ionic Channel Mechanism Underlies The Disappearance Of Frequency-Current(F-I) Relationship In Spinal Motoneurons During Locomotion

During locomotion,the excitability of the cat spinal cord motorneurons change drastically to adapt to the motion state.The Frequency-Current Relationship(F-I relationship)is an important feature descripting changes in excitability.It is usually shown as a left shift of the F-I curve or an increase in the slope of the F-I curve.These changes reflect the increase in the excitability of motorneurons during locomotion,as well as the changes in amplification of the gain of motorneurons input and output signals.There have been many studies reported about the alteration of F-I relationship during locomotion.The main conclusion is that modulation of multiple ion channels is the main mechanism underlying the changes in F-I relationship during locomotion.However,the results from cat experiments showed that about 25% of spinal cord motorneurons exhibited disappearance of the F-I relationship during locomotion,that is the firing frequency of motoneurons stabilizes at a higher frequency value and does not change with the injected current.In other words,the slope of the F-I curve is greatly reduced close to zero.The mechanism responsible for this phenomenon remains unknown,yet.Based on the above results,in this study we used modeling approach to study the ionic channel mechanism underlying the disappearance of the F-I relationship during locomotion.Using NEURON simulation software we built motoneuron model,based on the electrophysiological parameters of the cat spinal cord motorneurons.This model is a highly simplified spinal cord motorneuron in morphology and represented the S-type spinal cord motorneurons.The model included a soma compartment and four dendritic compartments(Dendrite 1-4).Seven of the most important ion channels of spinal motorneurons are included in the model,including the transient sodium channel(NaT),persistent sodium channel(NaP),delayed rectifier potassium channel(K(DR)),calcium-dependent potassium channel(K(AHP)),L-type calcium channel(CaL),N-type calcium channel(CaN)and H-current channel(H).This model can fully replicate the membrane properties of the S-type motorneurons.Using this model,we studied the effects of modulating channel conductance,either for a single ion channel or multiple ion channels,on the F-I relationship in either the resting state or the simulated locomotor state.The main results of the model simulation are shown as follows:? Reducing the conductance of the K(AHP)channel caused the disappearance of the F-I relationship in the resting state.? Except for the K(AHP)channel,none of the channel modulations could produce the disappearance of the F-I relationship.? Increasing the conductance of the CaL channel and reducing the conductance of the K(DR)channel led to the disappearance of the F-I relationship in the simulated locomotor state.? The disappearance of the F-I relationship induced by increasing the conductance of CaL channel and reducing the conductance of the K(DR)channel can be verified by pharmacological experiments,where the F-I relationship of spinal neurons disappeared after bath application of Bay K8644,the CaL channel against,and TEA,the K(DR)channel antagonist.The pharmacological experiments verified the results predicted by the model.Based on the above results,the conclusion of this study is that the disappearance of the F-I relationship of the cat lumbar motorneurons during locomotion could be generated by upregulation of CaL channel and downregulation of K(DR)channel.This study predicts the ion channel mechanism underlying the disappearance of the F-I relationship during locomotion,and it could lay a foundation for further study of this issue in the future.This study could also provide theoretical support from the channel mechanisms for the research of motion control and biomimetic robots.