A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance

Natsumi Ageta-Ishihara, Maya Yamazaki, Kohtarou Konno, Hisako Nakayama, Manabu Abe, Kenji Hashimoto, Tomoki Nishioka, Kozo Kaibuchi, Satoko Hattori, Tsuyoshi Miyakawa, Kohichi Tanaka, Fathul Huda, Hirokazu Hirai, Kouichi Hashimoto, Masahiko Watanabe, Kenji Sakimura and Makoto Kinoshita ()
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Natsumi Ageta-Ishihara: Nagoya University Graduate School of Science
Maya Yamazaki: Brain Research Institute, Niigata University
Kohtarou Konno: Hokkaido University Graduate School of Medicine
Hisako Nakayama: Graduate School of Biomedical and Health Sciences, Hiroshima University
Manabu Abe: Brain Research Institute, Niigata University
Kenji Hashimoto: Chiba University Center for Forensic Mental Health
Tomoki Nishioka: Nagoya University Graduate School of Medicine
Kozo Kaibuchi: Nagoya University Graduate School of Medicine
Satoko Hattori: Institute for Comprehensive Medical Science, Fujita Health University
Tsuyoshi Miyakawa: Institute for Comprehensive Medical Science, Fujita Health University
Kohichi Tanaka: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University
Fathul Huda: Gunma University Graduate School of Medicine
Hirokazu Hirai: Gunma University Graduate School of Medicine
Kouichi Hashimoto: Graduate School of Biomedical and Health Sciences, Hiroshima University
Masahiko Watanabe: Hokkaido University Graduate School of Medicine
Kenji Sakimura: Brain Research Institute, Niigata University
Makoto Kinoshita: Nagoya University Graduate School of Science

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: Abstract The small GTPase-effector proteins CDC42EP1-5/BORG1–5 interact reciprocally with CDC42 or the septin cytoskeleton. Here we show that, in the cerebellum, CDC42EP4 is exclusively expressed in Bergmann glia and localizes beneath specific membrane domains enwrapping dendritic spines of Purkinje cells. CDC42EP4 forms complexes with septin hetero-oligomers, which interact with a subset of glutamate transporter GLAST/EAAT1. In Cdc42ep4−/− mice, GLAST is dissociated from septins and is delocalized away from the parallel fibre-Purkinje cell synapses. The excitatory postsynaptic current exhibits a protracted decay time constant, reduced sensitivity to a competitive inhibitor of the AMPA-type glutamate receptors (γDGG) and excessive baseline inward current in response to a subthreshold dose of a nonselective inhibitor of the glutamate transporters/EAAT1–5 (DL-TBOA). Insufficient glutamate-buffering/clearance capacity in these mice manifests as motor coordination/learning defects, which are aggravated with subthreshold DL-TBOA. We propose that the CDC42EP4/septin-based glial scaffold facilitates perisynaptic localization of GLAST and optimizes the efficiency of glutamate-buffering and clearance.

Date: 2015
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DOI: 10.1038/ncomms10090

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