As a step in exploring the functions of the inferior olive, we constructed a biophysical model of the olivary neurons to examine their unique electrophysiological properties. The model consists of two compartments to represent the known distribution of ionic currents across the cell membrane, as well as the dendritic location of the gap junctions and synaptic inputs. The somatic compartment includes a low-threshold calcium current ( I Ca_l), an anomalous inward rectifier current ( I h), a sodium current ( I Na), and a delayed rectifier potassium current ( I K_dr). The dendritic compartment contains a high-threshold calcium current ( I Ca_h), a calcium-dependent potassium current ( I K_Ca), and a current flowing into other cells through electrical coupling ( I c). First, kinetic parameters for these currents were set according to previously reported experimental data. Next, the remaining free parameters were determined to account for both static and spiking properties of single olivary neurons in vitro. We then performed a series of simulated pharmacological experiments using bifurcation analysis and extensive two-parameter searches. Consistent with previous studies, we quantitatively demonstrated the major role of I Ca_l in spiking excitability. In addition, I h had an important modulatory role in the spike generation and period of oscillations, as previously suggested by Bal and McCormick. Finally, we investigated the role of electrical coupling in two coupled spiking cells. Depending on the coupling strength, the hyperpolarization level, and the I Ca_l and I hmodulation, the coupled cells had four different synchronization modes: the cells could be in-phase, phase-shifted, or anti-phase or could exhibit a complex desynchronized spiking mode. Hence these simulation results support the counterintuitive hypothesis that electrical coupling can desynchronize coupled inferior olive cells.
Y1767C, a Novel SCN5A Mutation Induces a Persistent Sodium Current and Potentiates Ranolazine Inhibition of NaV1.5 Channels
