Using realistic models to study synaptic integration in cerebellar Purkinje cells.

This review presents an approach to modeling which we call "experiments in computo". The use of realistic models makes it possible to generate new predictions that can be confirmed experimentally. Several examples are given of how this approach has improved our understanding of synaptic integration by the Purkinje cell active dendrite. The computer model was constructed to replicate neuronal behavior which has no direct relevance to synaptic integration: it was tuned to reproduce the response of Purkinje cells to current injection in vitro, which consists of a high frequency, regular rhythm of somatic Na+ spikes, interrupted by spontaneous dendritic Ca2+ spikes. The in vivo firing behavior of Purkinje cells is quite different as it consists of highly irregular simple spike firing only, without spontaneous dendritic Ca2+ spikes. The computer model predicted-that the Purkinje cell needs to receive a continuous background inhibitory synaptic drive in addition to the excitation by parallel fibers to obtain this typical in vivo firing. This prediction was confirmed by blocking inhibition during in vivo intracellular recordings. More recently, we demonstrated that the net inhibitory drive to the Purkinje cell dendrite has to be larger than the excitatory synaptic drive. Inhibition hyperpolarizes the dendrite compared to the soma, making it act as a current sink during most of the spiking cycle. These predictions have been confirmed with the dynamic clamp method in the cerebellar slice preparation. Synchronous focal excitatory input by parallel fiber leads in the model to activation of voltage-gated Ca2+ channels which amplify the somatic response by a variable amount. The variability of this graded amplification is due both to position of the input, effectively canceling the cable attenuation, and to the effect of preceding background input. Differences between the model and experimental results in this aspect can be explained by the relative hyperpolarized state of Purkinje cells in the in vitro experimental preparation. These studies led to a new theory about the function of long-term depression in the cerebellum which can explain recent experimental results. In conclusion, our modeling approach generated predictions which contradicted prevalent ideas on how the cerebellum, or neurons in general, works and led to experiments which otherwise would not have been carried out.