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The Journal of Neuroscience, May 18, 2005, 25(20):4930-4940; doi:10.1523/JNEUROSCI.0338-05.2005

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Cellular/Molecular
Modulation of Presynaptic Ca²⁺ Entry by AMPA Receptors at Individual GABAergic Synapses in the Cerebellum

Dmitri A. Rusakov,^1,2 * Fumihito Saitow,^1,3 * Knut P. Lehre,⁴ and Shiro Konishi^1,5

¹Molecular Neurobiology Laboratory, Mitsubishi Kagaku Institute of Life Sciences, and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo 194-8511, Japan, ²Institute of Neurology, University College London, London WC1N 3BG, United Kingdom, ³Department of Pharmacology, Nippon Medical School, Tokyo 113-8602, Japan, ⁴Centre for Molecular Biology and Neuroscience, University of Oslo, N-0317 Oslo, Norway, and ⁵Waseda-Olympus Bioscience Research Institute, Singapore 138667

Cerebellar Purkinje cells (PCs) receive GABAergic input that undergoes powerful retrograde modulation by presynaptic cannabinoid and glutamate receptors. Here we examine a distinct modulatory mechanism at these synapses, which does not require postsynaptic depolarization and acts via presynaptic AMPA receptors. We find that this mechanism operates mainly in the somatic vicinity of PCs in which large boutons of basket cell axons form synapses on the PC soma. We use fast confocal microscopy and detailed kinetic modeling to estimate that, in these boutons, an action potential opens 100-200 Ca²⁺ channels, eliciting a brief 3-5 µM transient, followed by a longer-term, 15-30 nM rise of free Ca²⁺ (above the resting level of 100 nM). Brief activation of local AMPA receptors suppresses Ca²⁺ entry (probably by silencing 20-40 P/Q-type channels) in a subgroup of terminals that tend to show a higher dynamic range of Ca²⁺ signaling. The results provide the first quantitative description of presynaptic Ca²⁺ kinetics and its modulation by AMPA receptor activation (most likely via a glutamate spillover-mediated mechanism) at identified GABAergic synapses.

Key words: presynaptic mechanisms; Ca²⁺ signaling; glutamate; spillover; AMPARs; cerebellum

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Received Jan 24, 2005; revised April 2, 2005; accepted April 7, 2005.

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