Variations in intracellular calcium concentration ([Ca²⁺]_i) provide a critical signal for synaptic plasticity. In accordance with Hebb's postulate (Hebb, 1949), an increase in postsynaptic [Ca²⁺]_ican induce bidirectional changes in synaptic strength depending on activation of specific biochemical pathways (Bienenstock et al., 1982; Lisman, 1989; Stanton and Sejnowski, 1989). Despite its strategic location for signal processing, spatiotemporal dynamics of [Ca²⁺]_ichanges and their relationship with synaptic plasticity at the cerebellar mossy fiber (mf)-granule cell (GrC) relay were unknown. In this paper, we report the plasticity/[Ca²⁺]_irelationship for GrCs, which are typically activated by mf bursts (Chadderton et al., 2004). Mf bursts caused a remarkable [Ca²⁺]_iincrease in GrC dendritic terminals through the activation of NMDA receptors, metabotropic glutamate receptors (probably acting through IP₃-sensitive stores), voltage-dependent calcium channels, and Ca²⁺-induced Ca²⁺release. Although [Ca²⁺]_iincreased with the duration of mf bursts, long-term depression was found with a small [Ca²⁺]_iincrease (bursts 250 ms). LTP and [Ca²⁺]_isaturated for bursts >500 ms and with theta-burst stimulation. Thus, bursting enabled a Ca²⁺-dependent bidirectional Bienenstock-Cooper-Munro-like learning mechanism providing the cellular basis for effective learning of burst patterns at the input stage of the cerebellum.

The function of inhibitory interneurons within brain microcircuits depends critically on the nature and properties of their excitatory synaptic drive. Golgi cells (GoCs) of the cerebellum inhibit cerebellar granule cells (GrCs) and are driven both by feedforward mossy fiber (mf) and feedback GrC excitation. Here, we have characterized GrC inputs to GoCs in rats and mice. We show that, during sustained mf discharge, synapses from local GrCs contribute equivalent charge to GoCs as mf synapses, arguing for the importance of the feedback inhibition. Previous studies predicted that GrC-GoC synapses occur predominantly between parallel fibers (pfs) and apical GoC dendrites in the molecular layer (ML). By combining EM and Ca(2+) imaging, we now demonstrate the presence of functional synaptic contacts between ascending axons (aa) of GrCs and basolateral dendrites of GoCs in the granular layer (GL). Immunohistochemical quantification estimates these contacts to be ∼400 per GoC. Using Ca(2+) imaging to identify synaptic inputs, we show that EPSCs from aa and mf contacts in basolateral dendrites display similarly fast kinetics, whereas pf inputs in the ML exhibit markedly slower kinetics as they undergo strong filtering by apical dendrites. We estimate that approximately half of the local GrC contacts generate fast EPSCs, indicating their basolateral location in the GL. We conclude that GrCs, through their aa contacts onto proximal GoC dendrites, define a powerful feedback inhibitory circuit in the GL.

Cerebellar neurones show complex and differentiated mechanisms of action potential generation that have been proposed to depend on peculiar properties of their voltage‐dependent Na⁺ currents. In this study we analysed voltage‐dependent Na⁺ currents of rat cerebellar granule cells (GCs) by performing whole‐cell, patch‐clamp experiments in acute rat cerebellar slices. A transient Na⁺ current (I_NaT) was always present and had the properties of a typical fast‐activating/inactivating Na⁺ current. In addition to I_NaT, robust persistent (I_NaP) and resurgent (I_NaR) Na⁺ currents were observed. I_NaP peaked at ∼−40 mV, showed half‐maximal activation at ∼−55 mV, and its maximal amplitude was about 1.5% of that of I_NaT. I_NaR was elicited by repolarizing pulses applied following step depolarizations able to activate/inactivate I_NaT, and showed voltage‐ and time‐dependent activation and voltage‐dependent decay kinetics. The conductance underlying I_NaR showed a bell‐shaped voltage dependence, with peak at −35 mV. A significant correlation was found between GC I_NaR and I_NaT peak amplitudes; however, GCs expressing I_NaT of similar size showed marked variability in terms of I_NaR amplitude, and in a fraction of cells I_NaR was undetectable. I_NaT, I_NaP and I_NaR could be accounted for by a 13‐state kinetic scheme comprising closed, open, inactivated and blocked states. Current‐clamp experiments carried out to identify possible functional correlates of I_NaP and/or I_NaR revealed that in GCs single action potentials were followed by depolarizing afterpotentials (DAPs). In a majority of cells, DAPs showed properties consistent with I_NaR playing a role in their generation. Computer modelling showed that I_NaR promotes DAP generation and enhances high‐frequency firing, whereas I_NaP boosts near‐threshold firing activity. Our findings suggest that special properties of voltage‐dependent Na⁺ currents provides GCs with mechanisms suitable for shaping activity patterns, with potentially important consequences for cerebellar information transfer and computation.