The mechanisms of late-onset synaptic responses in a realistic model of Unipolar Brush Cell

Unipolar brush cells (UBCs) are excitatory glutamatergic interneurons of the cerebellar granular layer receiving both primary and secondary vestibular inputs through mossy fibers (excitatory input) and Golgi cell axon (inhibitory input). When injected with a depolarizing current, the UBC generates a spike burst sustained by a low-threshold spike, which, at higher current intensity, is followed by a tonic firing showing frequency adaption. The intrinsic excitability of UBCs is characterized by an H current and by Low Voltage activated and High Voltage activated calcium currents. Fast inactivating T-type Calcium channels generate the low-threshold spikes while L-type Calcium channel sustain tonic firing. The H current (activating in the hyperpolarizing direction) produces a slow hyperpolarization characterized by a ”sag” and a rebound depolarization at the end of a depolarizing step. Here we present a biologically realistic multi-compartmental mathematical model of the UBC realized with the NEURON simulator. According to experimental data, the model includes 9 different ionic channels generating voltage-dependent A-type M-type BK-type and DR-type K currents, Na (transient, persistent and resurgent) currents, T-type and L-type Ca currents, the H-current and the TRP-current. These channels are sorted and distributed among compartments (soma, dendrite, and axon). The UBC model faithfully reproduces the excitable properties of real UBCs. In particular, the model includes mechanisms capable of reproducing the recently characterised "late onset response" (Locatelli et al., 2013). These mechanisms are based on the modulation of TRP- and Ih-channels by the activation of G-protein-dependent intracellular pathways yielding to the increase of cAMP concentration. 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