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The Journal of Neuroscience, June 14, 2006, 26(24):6563-6572; doi:10.1523/JNEUROSCI.5342-05.2006

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Cellular/Molecular
Glial Glutamate Transporters Maintain One-to-One Relationship at the Climbing Fiber–Purkinje Cell Synapse by Preventing Glutamate Spillover

Yukihiro Takayasu,^1,2 Masae Iino,¹ Keiko Shimamoto,³ Kohichi Tanaka,⁴ and Seiji Ozawa¹

Departments of ¹Neurophysiology and ²Otolaryngology, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan, ³Suntory Institute for Bioorganic Research, Mishima, Osaka, 618-8503, Japan, and ⁴Department of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan

Correspondence should be addressed to Dr. Yukihiro Takayasu, Department of Neurophysiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Email: takayasu{at}showa.gunma-u.ac.jp

A glial glutamate transporter, GLAST, is expressed abundantly in Bergmann glia and plays a major role in glutamate uptake at the excitatory synapses in cerebellar Purkinje cells (PCs). It has been reported that a higher percentage of PCs in GLAST-deficient mice are multiply innervated by climbing fibers (CFs) than in the wild-type (WT) mice, and that CF-mediated EPSCs with small amplitude and slow rise time, designated as atypical slow CF-EPSCs, are observed in these mice. To clarify the mechanism(s) underlying the generation of these atypical CF-EPSCs, we used (2S,3S)-3-[3-(4-methoxybenzoylamino)benzyloxy]aspartate (PMB-TBOA), an inhibitor of glial glutamate transporters. After the application of PMB-TBOA, slow-rising CF-EPSCs were newly detected in WT mice, and their rise and decay kinetics were different from those of conventional fast-rising CF-EPSCs but similar to those of atypical CF-EPSCs in GLAST-deficient mice. Furthermore, both slow-rising CF-EPSCs in the presence of PMB-TBOA in WT mice and atypical CF-EPSCs in GLAST-deficient mice showed much greater paired-pulse depression compared with fast-rising CF-EPSCs. In addition, both of them were more markedly inhibited by -D-glutamyl-glycine, a low-affinity competitive antagonist of AMPA receptors. These results indicated that both of these types of EPSCs were mediated by a low concentration of glutamate released from neighboring CFs. Based on all of these findings, we suggest that glial transporters prevent glutamate released from a single CF from spilling over to neighboring PCs other than the synaptically connected PC, and play an essential role in the maintenance of the functional one-to-one relationship between CFs and PCs.

Key words: glutamate transporter; GLAST; multiple innervation; climbing fiber; Purkinje cell; EPSC

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Received Dec. 14, 2005; revised May 5, 2006; accepted May 13, 2006.

Correspondence should be addressed to Dr. Yukihiro Takayasu, Department of Neurophysiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Email: takayasu{at}showa.gunma-u.ac.jp

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