Modulation of cellular mechanisms in a spinal locomotor network

Abstract: Neuronal networks generate behaviour. Thus, to understandbehaviour requires information on how neuronal networks work in termsof their cellular cornponents. The overall aim of this work has beento link proccsses occuring at an ionic level to the operation of aneural network specialized for undulatory locomotion. To this end, we have combined physiological experiments withcomputational techniques in the analysis, using the lamprey spinallocomotor network as a model system. The present study is focused onthe importance of membrane properties for the operation of the spinalneural network working through reciprocal inlhibition. In particular,the roles of low-voltage--activated (LVA) calcium currents and thedifferent subtypes of calcium--dependent potassium (KCa) currents forthe alternation between thc left and right hemisegment are examined. The influence of KCa channels on the burst rate depends not onlyon which subtype of KCa that is modulated but also how and to whatdegree this network is activated. The spinal network can be activatedby excitatory amino acids including, N-rnethyl-D aspartate (NMDA)which give rise to an alternating burst activity in a low-frequencyrange (0--3 Hz) whereas a burst range between 1-8 Hz is provided byan AMPA/kainate drive. A reduction of the conductance of the KCasubtype, responsible for the spike frequency adaptation, could eitherdecrease or increase the burst rate depending on the level ofAMPA/kainate used to drive the network. Moreover, when the network isdriven by NMDA the influence on the burst rate of this KCQ subtypedecline as the NMDA drive increasced as revealed both in experimentsand computer simulations. A reduction of the conductance of the otherKCa subtype instead increase the burst rate. Thus, one essentialfinding was the distinction between processes occurring with slowversus fast dynamics. This was found to apply both at a neuronallevel, in the analysis of neuronal membraue potential oscillations,along With the network level, as revealed by the different roles ofthe two subtypes of KCa conductances on the burst rate. This type of ion channel-cellular analysis is important as theoperation of neural networks is affected by neuromodulators whichtarget specific cellular mechanisms. Particularly GABA is describedin the present work. We show that GABA could play a modulatory rolein the regulation of the burst rate, the regularity of the burstpattern, and the intersegmental coordination between the spinalsegments. The cellular mechanisms underlying the modulation of theuetwork are also exarmined. Activation of GABAII re ceptors reducethe high--voltage-activated (HVA) calcium currernt and indirectly theKCa current (afterhypcerpolarization and frequency regulation), thusincreasing the gain of the conversion from synaptic input to a trainof action potentials. The tcefndency for post inhibitory rebounddepolarization is also reduced due to a decreased LVA calciumcurrent. By extending the neuronal simulation model with an LVAconductance we show that this will increase the reciprocalalternation rate on the network Ievel. Keywords: Neuronal Network, Calcium Channels, Calcium-DependentPotassium Channels, Neuronal Oscillator, Neuromodulation, GABAgreceptors, Lamprey, Locomotion, Spinal Cord, Computer Simulation