Dendritic distributions of L-type Ca and SK channels in spinal motoneurons: a simulation study.

Persistent inward currents are important to motoneuron excitability and firing behaviors and also have been implicated in excitotoxicity. In particular, L-type Ca channels, usually located on motoneuron dendrites, play a primary role in amplification of synaptic inputs. However, recent experimental findings on L-type Ca 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 Ca and SK channels. Specifically, the updated model incorporated asymmetric channel activation/deactivation kinetics, depolarization-dependent facilitation, randomness in channel gating, and coactivation of SK channels. Our simulation results suggest that L-type Ca and SK channels colocalize primarily on distal dendrites of motoneurons in a punctate expression. Also, punctate expression, as opposed to a homogeneous expression, provides high synaptic current amplification, limits bistability and firing rates, and robustly regulates the Ca 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 Ca channels' distal location and intrinsic warm-up. Accordingly, our results indicate that punctate expression of L-type Ca and SK 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. Recent experimental findings on L-type Ca channels challenge fundamental assumptions used in interpreting experimental and computational modeling data. Here, we incorporated recent experimental data into an updated, high-fidelity computational model to explain apparent inconsistencies and better elucidate the distributions, expression patterns, and functional roles of L-type Ca and SK channels. Our results indicate that punctate expression of L-type Ca and SK channels is a potent mechanism for regulating motoneuron excitability, providing a strong neuroprotective effect.