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The Journal of Neuroscience, February 22, 2006, 26(8):2278-2289; doi:10.1523/JNEUROSCI.4894-05.2006

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Cellular/Molecular
Characterization of AMPA Receptors Targeted by the Climbing Fiber Transmitter Mediating Presynaptic Inhibition of GABAergic Transmission at Cerebellar Interneuron-Purkinje Cell Synapses

Shin’Ichiro Satake,^1,2 Si-Young Song,² Qiong Cao,³ Hiromasa Satoh,⁴ Dmitri A. Rusakov,^2,5 Yuchio Yanagawa,⁶ Eng-Ang Ling,³ Keiji Imoto,¹ and Shiro Konishi⁴

¹National Institute for Physiological Sciences (NIPS), Okazaki 444-8787, Japan, ²Mitsubishi Kagaku Institute of Life Sciences, Tokyo 194-8511, Japan, ³National University of Singapore, 117597 Singapore, ⁴Waseda-Olympus Bioscience Research Institute, 138667 Singapore, ⁵Institute of Neurology, University College London, London WC1N 3BG, United Kingdom, and ⁶Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan

Correspondence should be addressed to either of the following: Keiji Imoto, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki 444-8787, Japan, Email: keiji{at}nips.ac.jp; or Shiro Konishi, Waseda-Olympus Bioscience Research Institute, Helios, 05-01/02, 11 Biopolis Way, 138667 Singapore, skonishi{at}waseda.jp

The climbing fiber (CF) neurotransmitter not only excites the postsynaptic Purkinje cell (PC) but also suppresses GABA release from inhibitory interneurons converging onto the same PC depending on AMPA-type glutamate receptor (AMPAR) activation. Although the CF-/AMPAR-mediated inhibition of GABA release provides a likely mechanism boosting the CF input-derived excitation, how the CF transmitter reaches target AMPARs to elicit this action remains unknown. Here, we report that the CF transmitter diffused from its release sites directly targets GluR2/GluR3 AMPARs on interneuron terminals to inhibit GABA release. A weak GluR3-AMPAR agonist, bromohomoibotenic acid, produced excitatory currents in the postsynaptic PCs without presynaptic inhibitory effect on GABAergic transmission. Conversely, a specific inhibitor of the GluR2-lacking/Ca²⁺-permeable AMPARs, philanthotoxin-433, did not affect the CF-induced inhibition but suppressed AMPAR-mediated currents in Bergmann glia. A low-affinity GluR antagonist, -D-glutamylglycine, or retardation of neurotransmitter diffusion by dextran reduced the inhibitory action of CF-stimulation, whereas blockade of glutamate transporters enhanced the CF-induced inhibition. The results suggest that the CF transmitter released after repeated stimulation overwhelms local glutamate uptake and thereby diffuses from the release site to reach GluR2/GluR3 AMPARs on nearby interneuron terminals. Double immunostaining showed that GluR2/3 subunits and glutamate decarboxylase or synaptophysin are colocalized at the perisomatic GABAergic processes surrounding PCs. Finally, electron microscopy detected specific immunoreactivity for GluR2/3 at the presynaptic terminals of symmetric axosomatic synapses on the PC. These findings demonstrate that the CF transmitter directly inhibits GABA release from interneurons to the PC, relying on extrasynaptic diffusion and local heterogeneity in AMPAR subunit compositions.

Key words: AMPA-type glutamate receptor; GABA; climbing fiber; basket cell; Bergmann glia; Purkinje cell; presynaptic inhibition; glutamate transporters; cerebellum

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Received July 19, 2005; revised Jan. 17, 2006; accepted Jan. 17, 2006.

Correspondence should be addressed to either of the following: Keiji Imoto, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki 444-8787, Japan, Email: keiji{at}nips.ac.jp; or Shiro Konishi, Waseda-Olympus Bioscience Research Institute, Helios, 05-01/02, 11 Biopolis Way, 138667 Singapore, skonishi{at}waseda.jp

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