Modeling action potential initiation using voltage-gated ion-channels kinetics from L5 pyramidal neurons of the rat cortex

Abstract

Discussion • Sodium currents were measured from L5 pyramidal neurons using six stimulation protocols in the nucleated and outside-out configurations of the patch-clamp technique and fit to several kinetic models of voltage-gated sodium channels. • Out of a dozen voltage-gated sodium channel (VGSC) models (only relevant configurations shown) it appears that the most simplified, a four-state-16-parameter, Hidden-Markov-Model (HMM) provides the best fit for the data. • The ability of the chosen HMM model to simulate generation and propagation of action potentials (APs) in L5 pyramidal neurons was tested relative to the most prevalent and complete model of morphological influence on firing pattern. • The combination of the simplified HMM and a Hodgkin-Huxley-like voltage-gated potassium channel model provides the best simile of high frequency bursts of APs in L5 pyramidal neurons. • Further development and investigation of an adequate voltage-gated potassium channel HMM is needed to replace the HH paradigm. • The chosen HMM should be further tested on other types of VGSCs from various neurons and compared to the performance of other HMM. Figure 1: Fitting Newly Devised Models to Experimentally Recorded Voltage-Gated Na+ Channels Currents from neocortical pyramidal neurons –results of fitting a data set containing five pulse protocols to the kinetic model formalisms shown in the insets. A, A 16 kinetic parameters model consisting of two closed states, an open state and an inactivated state, with the maximal conductance of each protocol providing an extra parameter. The transition rate functions were defined as kij=aij.ezij .Vm and kji=aji.e-zji .Vm for i<j. B, An example of the fit achieved by the model shown in A to activation traces consisting of inward currents recorded in the nucleated configuration of the patch-clamp technique that were produced by a 100 ms pre-pulse to -130 mV followed by a 20 ms pulse to voltages between -130 to -25 mV at 5 mV increments. C, A 32 kinetic parameters model consisting of three closed states, an open state and two inactivated states, the maximal conductances and transition rate functions were included as in A. D, The same data as in B fit with the model shown in C. 1 ms 100 pA B