Parameter tuning differentiates granule cell subtypes enriching transmission properties at the cerebellum input stage

Stefano Masoli, Marialuisa Tognolina et al. show that cerebellar granule cells do not respond uniformly to electrical stimuli. Using computational models and electrophysiology, they show that this diversity in granule cell response affects neurotransmitter release probabilities and can fine-tune cerebellar synaptic transmission. The cerebellar granule cells (GrCs) are classically described as a homogeneous neuronal population discharging regularly without adaptation. We show that GrCs in fact generate diverse response patterns to current injection and synaptic activation, ranging from adaptation to acceleration of firing. Adaptation was predicted by parameter optimization in detailed computational models based on available knowledge on GrC ionic channels. The models also predicted that acceleration required additional mechanisms. We found that yet unrecognized TRPM4 currents specifically accounted for firing acceleration and that adapting GrCs outperformed accelerating GrCs in transmitting high-frequency mossy fiber (MF) bursts over a background discharge. This implied that GrC subtypes identified by their electroresponsiveness corresponded to specific neurotransmitter release probability values. Simulations showed that fine-tuning of pre- and post-synaptic parameters generated effective MF-GrC transmission channels, which could enrich the processing of input spike patterns and enhance spatio-temporal recoding at the cerebellar input stage.