On the role of L-type Ca2+ and BK channels in a biophysical model of cartwheel interneurons

Cartwheel interneurons (CWCs) in the auditory system, which contribute to auditory processing and pathologies, exhibit a range of activity patterns, including bursting, spiking, and complex spiking. Although experiments have shown how these patterns can vary across individual neurons, the field has lacked a computational framework in which to explore the contributions of particular currents to these observations and to generate new predictions about the effects of pharmacological manipulations. We present a conductance-based CWC computational model, which captures the diversity of CWC activity patterns observed experimentally and suggests parameter changes that may underlie differences across cells. Specifically, we show using direct simulations and bifurcation diagrams that one parameter tuning yields a regular spiking phenotype in which the onset of activity, as input current is increased, takes the form of regular spiking and other tuning that gives a complex spiking phenotype in which bursting occurs at the spike onset and regular spiking only occurs over a narrow input range before it gives way to complex spiking. We next investigate the effects of the BK-type potassium current blocker iberiotoxin and the L-type calcium current blocker nifedipine. Our model reproduces the transitions to complex spiking and regular spiking, respectively, observed experimentally when these drugs are administered. In addition to the full model, we present a reduced model that preserves CWC dynamic regimes. We classify the reduced model variables in terms of distinct dynamic timescales and show that the key transitions in dynamic patterns under administration of iberiotoxin and nifedipine can be explained based on equilibria of the averaged dynamics of the slowest model variables, in a regime where the faster model variables exhibit oscillations. Overall, this study predicts how changes in parameters will influence CWC behavior, suggests how bifurcations contribute to changes in CWC dynamics, and provides a theoretical foundation that supports our simulation findings.