Bursting in cerebellar stellate cells induced by pharmacological agents: Non-sequential spike adding

Cerebellar stellate cells (CSCs) are spontaneously active, tonically firing (5-30 Hz), inhibitory interneurons that synapse onto Purkinje cells. We previously analyzed the excitability properties of CSCs, focusing on four key features: type I excitability, non-monotonic first-spike latency, switching in responsiveness and runup (i.e., temporal increase in excitability during whole-cell configuration). In this study, we extend this analysis by using whole-cell configuration to show that these neurons can also burst when treated with certain pharmacological agents separately or jointly. Indeed, treatment with (4-Aminopyridine) 4-AP, a partial blocker of delayed rectifier and A-type K+ channels, at low doses induces a bursting profile in CSCs significantly different than that produced at high doses or when it is applied at low doses but with cadmium (Cd2+), a blocker of high voltage-activated (HVA) Ca2+ channels. By expanding a previously revised Hodgkin–Huxley type model, through the inclusion of Ca2+-activated K+ (K(Ca)) and HVA currents, we explain how these bursts are generated and what their underlying dynamics are. Specifically, we demonstrate that the expanded model preserves the four excitability features of CSCs, as well as captures their bursting patterns induced by 4-AP and Cd2+. Model investigation reveals that 4-AP is potentiating HVA, inducing square-wave bursting at low doses and pseudo-plateau bursting at high doses, whereas Cd2+ is potentiating K(Ca), inducing pseudo-plateau bursting when applied in combination with low doses of 4-AP. Using bifurcation analysis, we show that spike adding in square-wave bursts is non-sequential when gradually changing HVA and K(Ca) maximum conductances, delayed Hopf is responsible for generating the plateau segment within the active phase of pseudo-plateau bursts, and bursting can become “chaotic” when HVA and K(Ca) maximum conductances are made low and high, respectively. These results highlight the secondary effects of the drugs applied and suggest that CSCs have all the ingredients needed for bursting.Author summary: Excitable cells, including neurons, fire action potentials (APs) in their membrane voltage that allow them to communicate with each other and to serve certain physiological purposes. They do so either tonically by firing APs periodically, or episodically by repeatedly firing clusters of APs (called bursts) separated by quiescent periods. Each one of those firing patterns can be neuron-specific and dependent on synaptic inputs and/or their physiological environment. Cerebellar stellate cells (CSCs) that synapse onto Purkinje cells, the sole output of the cerebellum responsible for motor control, are spontaneously active inhibitory interneurons that fire APs tonically. We previously studied the excitability properties of these neurons and showed that they possess several important key features, including type I excitability, runup, non-monotonic first spike latency and switching in responsiveness. In this study, we show that CSCs can also exhibit two modes of burst firing, called square-wave and pseudo-plateau, when treated with certain pharmacological agents. Using bifurcation theory, we demonstrate that spike adding in the square-wave burst is non-sequential, changing by several spikes when certain conductances are altered gradually. This study thus sheds lights onto the overall effects of the pharmacological agents and highlights the ability of CSCs to burst in certain biological conditions.