Parameter tuning differentiates granule cell subtypes enriching the repertoire of retransmission properties at the cerebellum input stage

Abstract

The cerebellar granule cells (GrCs) form an anatomically homogeneous neuronal population which, in its canonical description, discharges regularly without adaptation. We show here 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 GrC computational models based on the available knowledge on GrC ionic channels. The models also predicted that acceleration required the involvement of additional mechanisms. We found that yet unrecognized TRPM4 currents in accelerating GrCs could specifically account for firing acceleration. Moreover, adapting GrCs were better in transmitting high-frequency mossy fiber (MF) bursts over a background discharge than accelerating GrCs. This implied that different electroresponsive patterns corresponded to specific synaptic properties reflecting different neurotransmitter release probability. The correspondence of pre-and post-synaptic properties 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.

Computational models of neurotransmission at cerebellar synapses unveil the impact on network computation

“…with TRPM4 channels, which are primarily described in PCs (Kim et al, 2009(Kim et al, , 2013Menigoz et al, 2016). Remarkably, our model, derived from previous models (D 'Angelo et al, 2001;Nieus et al, 2006;Diwakar et al, 2009) and upgraded to account for sophisticated mechanisms of spike generation, predicted that TRPM4 currents, first recorded in GrCs, coupled to calmodulin through intracellular Ca 2+ changes, could effectively generate firing acceleration observed experimentally (Masoli et al, 2020b). Remarkably, mossy fiber-GrC synapse simulations showed that fine-tuning of adaptation/acceleration and short-term plasticity generated effective mossy fiber-GrC transmission channels, which could enrich the processing of incoming spike trains and enhance spatiotemporal coding at the cerebellar input stage (Gabbiani et al, 1994), according to the theoretical prediction of the adaptive filter model (Marr, 1969;Dean and Porrill, 2011;Rössert et al, 2015;D'Angelo et al, 2016).…”

“…In contrast to the canonical view describing GrCs as a homogenous population of neurons generating regular firing, our recently published work combining data from simulations and experimental findings on GrC electro responsive properties has identified different subtypes: adapting, non-adapting and accelerating GrCs (Masoli et al, 2020b). Adaptation occurs via Ca 2+ influx through high-threshold Ca 2+ conductance and subsequent increase in Ca 2+ -activated K + currents, causing an after-hyperpolarization potential after a burst of spikes (D'Angelo et al, 1998) whereas acceleration is correlated 2016)].…”

“…Interestingly, the realistic computational model of the granular layer network dynamics developed by Solinas et al (2010) established different roles for the main components of inhibition. Lateral inhibition is crucial for determining center-surface effects [GrCs in the core are more activated than those in the surrounding area (Mapelli and D'Angelo, 2007;D'Angelo and Casali, 2012;Prestori et al, 2019)], feed-forward inhibition to control the temporal window during which GrCs integrate excitatory inputs (D'Angelo and De Zeeuw, 2009;D'Angelo and Casali, 2012;Gandolfi et al, 2014;Eshra et al, 2019;Masoli et al, 2020b), and feedback inhibition to favor coherent oscillations in the theta frequency band (D'Angelo and Casali, 2012;Mapelli et al, 2014).…”

“…Moreover, the properties of specific AMPA receptor subtypes (gating kinetics and desensitization) determine the precision of spike emission, whereas the properties of NMDA receptor subunits (regulating gating kinetics, desensitization, and voltage-dependent Mg block) determine the intensity and duration of bursts. Another dimension is introduced by cell-to-cell variability, with differentiated excitable and neurotransmission properties even within the same class of neurons, [e.g., GrCs (Chabrol et al, 2015;Gilmer and Person, 2017;Masoli et al, 2020b;Straub et al, 2020), MLIs (Rizza et al, 2021), and candelabrum cells (Osorno et al, 2022), although not included in this work yet]. Finally, the strategic location of NMDA receptors at certain synapses (mossy fiber-GrC, mossy fiber-GoC, parallel fiber-PC, parallel fiber-MLI), as well as Ca permeation in certain types of AMPA receptors and voltage-gated calcium channels, causes various forms of plasticity that can further tune postsynaptic receptor conductance and presynaptic release probability, regulating the filtering properties of the circuit and local computations.…”

Cellular-resolution mapping uncovers spatial adaptive filtering at the cerebellum input stage

“…These simulations therefore strongly support the concept that mossy fiber -granule cell plasticity is fundamental to tune the filtering properties of the cerebellar granular layer. The recently discovered granule cell subtypes (adapting, nonadapting and accelerating) may further bias the unit toward high-pass or low-pass filtering depending on the expression of TRPM4 channels 45 .…”