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Contribution of Postsynaptic GluD2 to Presynaptic R-type Ca2+ Channel Function, Glutamate Release and Long-term Potentiation at Parallel Fiber to Purkinje Cell Synapses

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Abstract

Glutamate-receptor-like molecule delta2 (GluD2) is selectively expressed on the postsynaptic membranes at parallel fiber to Purkinje cell (PF-PC) synapses in the cerebellum. GluD2 plays critical roles not only in postsynaptic long-term depression but also in the induction of presynaptic differentiation through trans-synaptic interaction with neurexin. However, how GluD2 influences the presynaptic function remains unknown. Here, effects of the deletion of postsynaptic GluD2 on the presynaptic properties were studied focusing on the paired pulse ratio (PPR) of two consecutive EPSC amplitudes, which was larger in GluD2 knockout mice. The PPR difference remained even if saturation of glutamate binding to postsynaptic receptors was suppressed, confirming the presynaptic difference between the genotypes. We then explored the possibility that presynaptic voltage-gated Ca2+ channels (VGCCs) are affected in GluD2 knockout mice. Application of selective blockers for specific VGCCs indicated that R-type but not P/Q- or N-type VGCC, was affected in the mutant mice. Furthermore, presynaptic long-term potentiation (LTP) at PF-PC synapses, which requires R-type VGCC, was impaired in GluD2 knockout mice. These results suggest that GluD2 deletion impairs presynaptic R-type VGCC, resulting in decreased release of synaptic vesicles, and also in the impairment of presynaptic LTP at PF-PC synapses.

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Acknowledgments

We thank Y. Tagawa, G. Ohtsuki, and E. Nakajima for comments on the manuscript. This work was supported by a grant-in-aid for scientific research and by a grant for excellent graduate schools from the Ministry of Education, Culture, Sports, Science and Technology in Japan, Takeda Science Foundation, and also by Global COE program A06 of Kyoto University.

Conflict of Interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto, 606-8502, Japan

    Manami Yamashita, Shin-ya Kawaguchi & Tomoo Hirano

  2. Graduate School of Brain Science, Doshisha University, Kizugawa, Kyoto, 619-0225, Japan

    Shin-ya Kawaguchi

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  1. Manami Yamashita
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  2. Shin-ya Kawaguchi
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Correspondence to Tomoo Hirano.

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Supplemental Fig. 1

Effects of DGG on the EPSC amplitude. a, b The decrease in EPSC amplitude caused by application of 2 mM DGG in wild-type (“+/+” n = 5; a) and GluD2 knockout (“−/−” n = 5; b) mice (JPEG 9 kb)

High-resolution image (TIFF 99 kb)

Supplemental Fig. 2

The time courses of EPSC amplitude change when [Ca2+]o was increased in wild-type (“+/+” open circles, n = 5) and in knockout (“−/−” filled circles, n = 5) mice (JPEG 12 kb)

High-resolution image (TIFF 79 kb)

Supplemental Fig. 3

PPR with various intervals in the presence of both Ni2+ and DGG in wild-type (“+/+” open circles, n = 9) and in knockout (“−/−” filled circles, n = 9) mice (JPEG 7 kb)

High-resolution image (TIFF 51 kb)

Supplemental Fig. 4

Effects of a cocktail of antagonists for A1R, GABABR, and CB1R. Application of the cocktail increased the EPSC amplitude both in wild-type (“+/+” open circles, n = 5) and in knockout (“−/−” filled circles, n = 5) mice (JPEG 14 kb)

High-resolution image (TIFF 74 kb)

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Yamashita, M., Kawaguchi, Sy. & Hirano, T. Contribution of Postsynaptic GluD2 to Presynaptic R-type Ca2+ Channel Function, Glutamate Release and Long-term Potentiation at Parallel Fiber to Purkinje Cell Synapses. Cerebellum 12, 657–666 (2013). https://doi.org/10.1007/s12311-013-0474-y

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