Integration of Cellular Metabolism and Membrane Excitability in Cerebellar Purkinje Neurons

Abstract

Calcium and membrane physiology are crucial to cerebellar Purkinje neuron function. Purkinje cell physiology involves phosphoinositide/calcium signaling and calcium influx through voltage-gated calcium channels, as well as potassium efflux through (i) voltage-gated, and (ii) calcium-activated voltage-gated channels (primarily the BK channel). The interaction between phosphoinositide-induced calcium signaling and calcium-activated/voltage-gated potassium channels have not been explored extensively. We have developed computational models to explore the integration of these mechanisms. We used an electrophysiological model in NEURON to parameterize a compartmental Virtual Cell (VCell) model. We then combined our published calcium metabolism model (created in VCell) with the electrophysiological model. We investigated the influence of IP3R1-mediated calcium release from smooth endoplasmic reticulum close to the plasma membrane on the activity of the BK channel and thus on membrane potential. The model predicts that supralinear IP3R1-mediated calcium release into a submembrane shell can activate BK channels. When coupled with synaptic conductance changes, this activation of the BK channels increases the rate of repolarization (RR) of the spine. As the voltage changes in the spine propagate to the soma, the corresponding RR in the soma is also increased. Simulation of IP3R1 ko abolishes any increase in the RR in both the spine and the soma. Reduced IP3R1 abundance (as found in some cerebellar ataxias; in model, 10% - 50% of the original value), almost completely abolishes any increase in the RR, in both spine and soma. Increasing the sensitivity of IP3R1 to IP3 restores normal IP3R1-mediated calcium, and restores increased activation of the BK channels. The resulting RR of both the spine and the soma are also restored. These results suggest that the BK channel may play a role in integrating signals from cellular metabolism and membrane excitability. (Supported by NIH P41 RR013186)