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

• DOI: 10.1371/journal.pcbi.1008463
• Publication Date: 2020-12-14T18:48:37Z
• Authors: Saeed Farjami; Ryan P. D. Alexander; Derek Bowie; Anmar Khadra
• Keywords: 0303 health sciences; Patch-Clamp Techniques; Dose-Response Relationship, Drug; QH301-705.5; Action Potentials; Calcium Channel Blockers; Models, Biological; Mice, Inbred C57BL; Mice; Purkinje Cells; 03 medical and health sciences; Cerebellum; Potassium Channel Blockers; Animals; Biology (General); 4-Aminopyridine; Research Article; Cadmium

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.