Inositol 1,4,5-Trisphosphate-Dependent Ca2+Threshold Dynamics Detect Spike Timing in Cerebellar Purkinje Cells

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Abstract
Large Ca2+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 Ca2+signals and/or LTD can also be induced by massive PF stimulation alone or by photolysis of caged Ca2+or inositol 1,4,5-trisphosphate (IP3). To understand the spike-timing detection mechanisms in cerebellar LTD, we developed a kinetic model of Ca2+dynamics within a Purkinje dendritic spine. In our kinetic simulation, IP3was first produced via the metabotropic pathway of PF inputs, and the Ca2+influx in response to the CF input triggered regenerative Ca2+-induced Ca2+release from the internal stores via the IP3receptors activated by the increased IP3. The delay in IP3increase caused by the PF metabotropic pathway generated the optimal PF-CF interval. The Ca2+dynamics revealed a threshold for large Ca2+release that decreased as IP3increased, and it coherently explained the different forms of LTD. At 2.5 μmIP3, CF activation after PF activation was essential to reach the threshold for the regenerative Ca2+release. At 10 μmIP3, the same as achieved experimentally by strong IP3photolysis, the threshold was lower, and thus large Ca2+release was generated even without CF stimulation. In contrast, the basal 0.1 μmIP3level resulted in an extremely high Ca2+threshold for regenerative Ca2+release. Thus, the results demonstrated that Ca2+dynamics can detect spike timing under physiological conditions, which supports cerebellar learning theories.