Intracellular calcium regulation by burst discharge determines bidirectional long-term synaptic plasticity at the cerebellum input stage

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+]i can 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+]i changes 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+]i relationship for GrCs, which are typically activated by mf bursts (Chadderton et al., 2004). Mf bursts caused a remarkable [Ca2+]i increase 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+]i increased with the duration of mf bursts, long-term depression was found with a small [Ca2+]i increase (bursts 250 ms). LTP and [Ca2+]i saturated 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