Analysis of upper threshold mechanisms of spherical neurons during extracellular stimulation

Exceeding a certain stimulation strength can prevent the generation of somatic action potentials, as has been demonstrated in vitro with extracellularly stimulated dorsal root ganglion cells as well as retinal ganglion cells. This phenomenon, termed upper threshold, is currently thought to be a consequence of sodium current reversal in strongly depolarized regions. Here we analyze the contribution of membrane kinetics, using spherical model neurons that are stimulated externally with a microelectrode, in more detail. During extracellular pulse application, the electric field depolarizes one part and hyperpolarizes the other part of the cell. Strong transmembrane currents are generated only in the active depolarized region, changing the overall polarization level. The asymmetric membrane voltage distribution caused by the stimulus strongly influences the cell's behavior during and even after the stimulus. Effects on membrane voltage and transmembrane currents during and after the stimulus are shown and discussed in detail. Aside from the sodium current reversal, two more key mechanisms were identified in causing the upper threshold: strong potassium currents and inactivation of sodium channels. The contributions of the mechanisms involved strongly depend on cell properties, stimulus parameters, and other factors such as temperature. The conclusions presented here are based on several retinal ganglion cell models of the Fohlmeister group, a model with original Hodgkin-Huxley membrane, and a pyramidal cell model. NEW & NOTEWORTHY The upper threshold phenomenon in extracellular stimulation is analyzed in detail for spherical cells. Three main mechanisms were identified that prevent the generation of action potentials at high stimulation strengths: 1) strong potassium currents, 2) inactivating sodium ion channels, and 3) sodium current reversal. Ion channel kinetics in retinal ganglion cells, pyramidal cells, and the original Hodgkin-Huxley model were investigated under the influence of an extracellular stimulus.