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Cerebellar long-term depression requires dephosphorylation of TARP in Purkinje cells

Authors

  • Toshihiro Nomura,

    1. Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
    2. Department of Pediatrics, School of Medicine, Keio University, Tokyo, Japan
    3. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Saitama, Japan
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  • Wataru Kakegawa,

    1. Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
    2. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Saitama, Japan
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  • Shinji Matsuda,

    1. Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
    2. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Saitama, Japan
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  • Kazuhisa Kohda,

    1. Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
    2. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Saitama, Japan
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  • Jun Nishiyama,

    1. Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
    2. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Saitama, Japan
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  • Takao Takahashi,

    1. Department of Pediatrics, School of Medicine, Keio University, Tokyo, Japan
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  • Michisuke Yuzaki

    1. Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
    2. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Saitama, Japan
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Dr M. Yuzaki, 1Department of Physiology, as above.
E-mail: myuzaki@a5.keio.jp

Abstract

Cerebellar long-term depression (LTD) at parallel fiber (PF)–Purkinje cell synapses is thought to play an essential role in certain forms of motor learning. Like hippocampal LTD, cerebellar LTD is mediated by the endocytosis of AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) receptors at postsynaptic sites. However, similar sets of kinases and phosphatases have opposite regulatory effects on hippocampal and cerebellar LTD, although the mechanisms responsible for this difference remain largely unclear. Activity-dependent dephosphorylation of stargazin (an AMPA receptor auxiliary protein) by calcineurin regulates hippocampal LTD, but whether and how stargazin is involved in cerebellar LTD is unknown. In this study, we showed that stargazin is highly phosphorylated at basal states and is dephosphorylated by the application of high KCl plus glutamate (K-glu) or of a metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine (DHPG), both of which chemically induced LTD in cerebellar slices. This chemically induced dephosphorylation of stargazin was specifically blocked by a calcineurin inhibitor. Indeed, inclusion of the calcineurin auto-inhibitory peptide in the patch pipette solution completely inhibited the LTD induced by the conjunctive stimulation of PFs and Purkinje cells. Furthermore, in Purkinje cells expressing stargazin-9D, in which all nine serine residues are mutated to aspartate, neither conjunctive stimulus nor DHPG treatment induced LTD. Finally, immunohistochemical analyses revealed that neither K-glu nor DHPG induced the endocytosis of AMPA receptors in Purkinje cells expressing stargazin-9D. Together, these results indicate that hippocampal and cerebellar LTD share a common pathway, namely dephosphorylation of stargazin by calcineurin.

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