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The Journal of Neuroscience, January 26, 2005, 25(4):950-961; doi:10.1523/JNEUROSCI.2727-04.2005

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

Tomokazu Doi,^1,2 Shinya Kuroda,^3,4 Takayuki Michikawa,⁵ and Mitsuo Kawato¹

¹ATR Computational Neuroscience Laboratories, Kansai Science City, Kyoto 619-0288, Japan, ²Graduate School of Information Science, Nara Institute of Science and Technology, Ikoma-shi, Nara 630-0192, Japan, ³Undergraduate Program for Bioinformatics and Systems Biology, Graduate School of Information Science and Technology, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, ⁴Precursory Research for Embryonic Science and Technology, Japan Science and Technology, Bunkyo-ku, Tokyo 113-0033, Japan, and ⁵Division of Molecular Neurobiology, Department of Basic Medical Science, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

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, IP₃ was 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 IP₃ receptors activated by the increased IP₃. The delay in IP₃ increase 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 IP₃ increased, and it coherently explained the different forms of LTD. At 2.5 µM IP₃, CF activation after PF activation was essential to reach the threshold for the regenerative Ca²⁺ release. At 10 µM IP₃, the same as achieved experimentally by strong IP₃ photolysis, the threshold was lower, and thus large Ca²⁺ release was generated even without CF stimulation. In contrast, the basal 0.1 µM IP₃ level 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.

Key words: calcium; LTD; simulation; timing detection; inositol; feedback

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Received July 8, 2004; revised December 3, 2004; accepted December 4, 2004.

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