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.

Long-term synaptic plasticity, in the form of either potentiation or depression (LTP or LTD), is thought to provide the substrate for adaptive computations in brain circuits. Although molecular and cellular processes of plasticity have been clarified to a considerable extent at individual synapses, very little is known about the spatiotemporal organization of LTP and LTD in local microcircuits. Here, we have combined multi-spot two-photon laser microscopy and realistic modeling to map the distribution of plasticity in multi-neuronal units of the cerebellar granular layer activated by stimulating an afferent mossy fiber bundle. The units, composed by ~300 active neurons connected to ~50 glomeruli, showed potentiation concentrated in the core and depression in the periphery. This plasticity was effectively accounted for by an NMDA receptor and calcium-dependent induction rule and was regulated by local microcircuit mechanisms in the inhibitory Golgi cell loops. The organization of LTP and LTD created effective spatial filters tuning the time-delay and gain of spike retransmission at the cerebellum input stage and provided a plausible basis for the spatiotemporal recoding of input spike patterns anticipated by the motor learning theory.recording activity from several granular layer neurons simultaneously and was stable enough to monitor long-term changes in synaptic transmission 25 . Therefore, in principle, SLM-2PM should allow to map spatially distributed granular layer activity with single cell resolution before and after the induction of long-term synaptic plasticity with high-frequency mossy fiber stimuli [26][27][28][29] . A further critical step is to extract the single spike patterns of neurons, which cannot be directly measured at the time resolution of calcium imaging but can be inferred using realistic modeling techniques. In recent years, modeling of the granular layer has advanced enough to guarantee a good predictability of local microcircuit dynamics [30][31][32] . Techniques are therefore mature, in principle, to evaluate the cellular determinates of the adaptive filtering properties predicted by theory in computational units of the cerebellum granular layer. RESULTS Multi-neuron responses of the granular layer following mossy fiber stimulationCalcium imaging (with Fura-2 AM) was performed using a spatial light modulator twophoton microscope (SLM-2PM) 25 in order to gain insight into the cellular organization of granular layer responses to MF bundle stimulation in acute cerebellar slices. We recorded up to 200 granule cells simultaneously, many of which (normally <=100) responded with fluorescence changes following delivery of short stimulus bursts (10 pulses @ 50 Hz) ( Fig.1 A-C). Recordings were carried out both on the sagittal and coronal plane, in order to account for potential asymmetries in granular layer responses. The multi-neuron maps (∆F/F 0 of granule cell responses to MF stimulation) covered a surface that was irregularly rounded both in sagittal and coronal slices and showed activity de...