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), and long- term potentiation ( LTP) was found with a large [ 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.