Non-Technical Summary The property of excitability is conferred to specific cell types through the action of a host of ion channels. Two classes of ion channels which play crucial roles in cellular excitability are T-type calcium and hyperpolarization-activated cyclic-nucleotide (HCN) channels. Given that T-type and HCN channel availability is increased upon hyperpolarization, T-type- and HCN-mediated currents are critical determinants of rebound depolarizations in many cell types. Rebound responses have long been documented in deep cerebellar nuclear (DCN) neurons; however, the extent to which T-type- and HCN-mediated currents contribute to rebound depolarizations following physiological input has not been established. Using a combination of in vitro electrophysiological and in silico techniques, we define the roles of T-type- and HCN-mediated currents in controlling the frequency and latency of DCN rebound spike output. Our study demonstrates that T-type and HCN channels become sufficiently available during physiological levels of hyperpolarization to make distinct contributions to the frequency and latency of rebound responses.
Abstract The ability for neurons to generate rebound bursts following inhibitory synaptic input relies on ion channels that respond in a unique fashion to hyperpolarization. Inward currents provided by T-type calcium channels (IT) and hyperpolarization-activated HCN channels (IH) increase in availability upon hyperpolarization, allowing for a rebound depolarization after a period of inhibition. Although rebound responses have long been recognized in deep cerebellar nuclear (DCN) neurons, the actual extent to which IT and IH contribute to rebound spike output following physiological levels of membrane hyperpolarization has not been clearly established. The current study used recordings and simulations of large diameter cells of the in vitro rat DCN slice preparation to define the roles for IT and IH in a rebound response. We find that physiological levels of hyperpolarization make only small proportions of the total IT and IH available, but that these are sufficient to make substantial contributions to a rebound response. At least 50% of the early phase of the rebound spike frequency increase is generated by an IT-mediated depolarization. An additional frequency increase is provided by IH in reducing the time constant and thus the extent of IT inactivation as the membrane returns from a hyperpolarized state to the resting level. An IH-mediated depolarization creates an inverse voltage-first spike latency relationship and produces a 35% increase in the precision of the first spike latency of a rebound. IT and IH can thus be activated by physiologically relevant stimuli and have distinct roles in the frequency, timing and precision of rebound responses.