Potassium channels and PKC activation underlying temporal specificity of classical conditionin

This computational study is to investigate the properties of the transient potassium current (IA) and the PKC activation of classical conditioning in cerebellar Purkinje cells. The role of the ( IA) in regulating cell excitability is generally accepted. More recently experiments show that an IA-like current plays a role in the generation of dendritic calcium spikes in Purkinje cells, and may mediate learning-specific changes in Purkinje cell membrane excitability (Schreurs et al., 1998). In this study, the role of the transient potassium current is further investigated using a physiologically realistic model of a cerebellar Purkinje cell. A detailed compartmental model of a cerebellar Purkinje cell (De Schutter and Bower, 1994a, b) is modified to improve the similarity between simulated and measured Purkinje cell behavior: IA channels are added to thick and spiny dendrites, and kinetics of the IA channels, the P-type calcium channels (ICaP), and the high threshold calcium-activated potassium channels (IKC) are modified. These modifications increase the dendritic spike latency to several hundred msec, comparable to that observed in the slice.;Simulations of Schreurs et al. [88] experiments: when the maximum conductance of IA (gKA) is reduced to 40% of its control value or the half activation voltage is increased by 3 mV, the current required to elicit dendritic spike is decreased by 22%, comparable to that observed in classically conditioned rabbits. Additional simulations show that IA channels should be located in thick and spiny dendrites in Purkinje cells and IA channel inactivation must be hundreds, not tens of msec, demonstrating that kinetics of the Purkinje cell IA channel are atypical. The aim of this study is investigating the cellular basis of classical conditioning, specifically the role of PKC and the transient potassium channel in cerebellar purkinje cells.;Protein kinase C (PKC) activation is a biochemical reaction involved in classical conditioning. This study also investigates the time-varying concentration of the second messengers leading from metabotropic glutamate (mGlu) to PKC activation during classical conditioning. The differential equations describing the cascade of the biochemical reactions are derived and implemented. Simulations show that diacylglycerol (DAG) and arachidonic acid (AA) are required for PKC activation as shown in [51, 96, 69]. Additional simulations show that a transient active form of PKC (tPKC) is elevated when both DAG and Ca2+ are elevated; a persistent active form of PKC (pPKC) is elevated when both DAG and AA are elevated. Then, the model simulations are used to evaluate the temporal specificity of PKC activation and the sensitivity of PKC activation to the ISI of classical conditioning. Simulations at different interstimulus interval (ISI) in the single compartment show that if parallel fiber (PF) stimulation precedes climbing fiber (CF) stimulation by 300 msec, PKC activation is elevated. Simulations using a single compartment model show that PKC activation is higher when parallel fiber stimulation precedes climbing fiber stimulation by 300 msec than when CF precedes PF by 100 msec. Furthermore, simulations using a multi-compartment model show that the PKC activation is higher when paired stimulations of PF and CF applied than when unpaired stimulation of CF and PF are applied.