Inositol 1,4,5-Trisphosphate-Dependent Ca 2+ Threshold Dynamics Detect Spike Timing in Cerebellar Purkinje Cells

Large Ca 2+ signals essential for cerebellar long-term depression (LTD) at parallel fiber (PF)-Purkinje cell synapses are known to be induced when PF activation precedes climbing fiber (CF) activation by 50-200 ms, consistent with cerebellar learning theories. However, large Ca 2+ signals and/or LTD can also be induced by massive PF stimulation alone or by photolysis of caged Ca 2+ or inositol 1,4,5-trisphosphate (IP 3 ). To understand the spike-timing detection mechanisms in cerebellar LTD, we developed a kinetic model of Ca 2+ dynamics within a Purkinje dendritic spine. In our kinetic simulation, IP 3 was first produced via the metabotropic pathway of PF inputs, and the Ca 2+ influx in response to the CF input triggered regenerative Ca 2+ -induced Ca 2+ release from the internal stores via the IP 3 receptors activated by the increased IP 3 . The delay in IP 3 increase caused by the PF metabotropic pathway generated the optimal PF-CF interval. The Ca 2+ dynamics revealed a threshold for large Ca 2+ release that decreased as IP 3 increased, and it coherently explained the different forms of LTD. At 2.5 μ m IP 3 , CF activation after PF activation was essential to reach the threshold for the regenerative Ca 2+ release. At 10 μ m IP 3 , the same as achieved experimentally by strong IP 3 photolysis, the threshold was lower, and thus large Ca 2+ release was generated even without CF stimulation. In contrast, the basal 0.1 μ m IP 3 level resulted in an extremely high Ca 2+ threshold for regenerative Ca 2+ release. Thus, the results demonstrated that Ca 2+ dynamics can detect spike timing under physiological conditions, which supports cerebellar learning theories.