Dendritic distributions of L-type Ca2+ and SKL channels in spinal motoneurons: A simulation study.

Mousa, Mohamed H; Elbasiouny, Sherif M

Persistent inward currents are important to motoneuron excitability and firing behaviors, and also have been implicated in excitotoxicity. In particular, L-type Ca2+ channels, usually located on motoneuron dendrites, play a primary role in amplification of synaptic inputs. However, recent experimental findings on L-type Ca2+ channel behaviors challenge some fundamental assumptions that have been used in interpreting experimental and computational modeling data. Thus, the objectives of this study were to incorporate recent experimental data into an updated, high-fidelity computational model in order to explain apparent inconsistencies, and to better elucidate the spatial distributions, expression patterns, and functional roles of L-type Ca2+ and SKL channels. Specifically, the updated model incorporated asymmetric channel activation/deactivation kinetics, depolarization-dependent facilitation, randomness in channel gating, and coactivation of SKL channels. Our simulation results suggest that L-type Ca2+ and SKL channels co-localize primarily on distal dendrites of motoneurons, in a punctate expression. Also, punctate expression, as opposed to a homogenous expression, provides high synaptic current amplification, limits bistability and firing rates, and robustly regulates the Ca2+ persistent inward current, thereby reducing risk of excitotoxicity. The hysteresis and bistability observed experimentally in current/voltage and frequency/current relationships result from the L-type Ca2+ channels' distal location and intrinsic warm-up. Accordingly, our results indicate that punctate expression of L-type Ca2+ and SKL channels is a potent mechanism for regulating excitability, which would provide a strong neuroprotective effect. Our results could provide broader insights into the functional significance of warm-up and punctate expression of ion channels to regulation of cell excitability.