Multiple bursting evoked by mossy fiber bundle stimulation in Unipolar Brush Cell: Experimental evidence and computational modeling.

Synaptic transmission at central synapses has usually short latency and graded amplitude, thereby regulating threshold crossing and the probability of action potential generation. In the granular layer of vestibulo-cerebellum, the unipolar brush cells (UBCs) receive a giant synapse generating a stereotyped EPSP-burst complex with early-onset (~ 2 ms) and high reliability. By using patch-clamp recordings in cerebellar slices of the rat vestibulo-cerebellum, we found that mossy fiber bundle stimulation also evoked (in ~70% of cases) a late-onset burst (tens to hundreds of milliseconds) independent from EPSP generation. Different from the early-onset, the late-onset burst delay decreased and its duration increased by raising stimulation intensity or the number of impulses. Although depending on synaptic activity, the late-onset response was insensitive to APV, NBQX and MCPG perfusion and did not therefore depend on conventional glutamatergic transmission mechanisms. The late-onset response was initiated by a slow depolarizing ramp driven by activation of an H-current (sensitive to ZD7288- and Cs2+) and of a TRP-current (sensitive to SKF96365), was occluded by cAMP, while the HVA and LVA Ca2+-currents (sensitive to nimodipine and mibefradil) played a negligible role These results indicate that afferent activity can regulate H- and TRP-current gating in UBCs generating synaptically-driven EPSP-independent responses, in which the delay rather than amplitude is graded with the intensity of the input pattern. This modality of synaptic transmission may play an important role for regulating UBC activation and granular layer functions in the vestibulo-cerebellum. Moreover, here we present a biologically realistic multi-compartmental mathematical model of the UBC realized with the NEURON simulator. This model is able to reproduce the excitable properties of UBCs in current-clamp and voltage-clamp modes. Attempts at modeling the response to mossy fiber inputs are ongoing. This model, in addition to confirm the primary role of the aforementioned currents in UBC’s electroresponsiveness, will prove a valuable tool for investigating the UBC’s function in the cerebellar network