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 Takai, Tsuyoshi Miyakawa, Kohichi Tanaka, Fathul Huda, Hirokazu Hirai, Kouichi Hashimoto, Masahiko Watanabe, Kenji Sakimura, Makoto Kinoshita

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 (Î 3DGG) 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.

Original languageEnglish
Article number10090
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 10-12-2015

Fingerprint

Septins
glutamates
clearances
Scaffolds
Neuroglia
Glutamic Acid
Fermi Gamma-ray Space Telescope
Amino Acid Transport System X-AG
Purkinje Cells
transporter
inhibitors
mice
Dendritic Spines
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
AMPA Receptors
Monomeric GTP-Binding Proteins
Excitatory Postsynaptic Potentials
cerebellum
Glutamate Receptors
effectors

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Ageta-Ishihara, N., Yamazaki, M., Konno, K., Nakayama, H., Abe, M., Hashimoto, K., ... Kinoshita, M. (2015). A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance. Nature Communications, 6, [10090]. https://doi.org/10.1038/ncomms10090
Ageta-Ishihara, Natsumi ; Yamazaki, Maya ; Konno, Kohtarou ; Nakayama, Hisako ; Abe, Manabu ; Hashimoto, Kenji ; Nishioka, Tomoki ; Kaibuchi, Kozo ; Takai, Satoko ; Miyakawa, Tsuyoshi ; Tanaka, Kohichi ; Huda, Fathul ; Hirai, Hirokazu ; Hashimoto, Kouichi ; Watanabe, Masahiko ; Sakimura, Kenji ; Kinoshita, Makoto. / A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance. In: Nature Communications. 2015 ; Vol. 6.
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author = "Natsumi Ageta-Ishihara and Maya Yamazaki and Kohtarou Konno and Hisako Nakayama and Manabu Abe and Kenji Hashimoto and Tomoki Nishioka and Kozo Kaibuchi and Satoko Takai and Tsuyoshi Miyakawa and Kohichi Tanaka and Fathul Huda and Hirokazu Hirai and Kouichi Hashimoto and Masahiko Watanabe and Kenji Sakimura and Makoto Kinoshita",
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Ageta-Ishihara, N, Yamazaki, M, Konno, K, Nakayama, H, Abe, M, Hashimoto, K, Nishioka, T, Kaibuchi, K, Takai, S, Miyakawa, T, Tanaka, K, Huda, F, Hirai, H, Hashimoto, K, Watanabe, M, Sakimura, K & Kinoshita, M 2015, 'A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance', Nature Communications, vol. 6, 10090. https://doi.org/10.1038/ncomms10090

A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance. / Ageta-Ishihara, Natsumi; Yamazaki, Maya; Konno, Kohtarou; Nakayama, Hisako; Abe, Manabu; Hashimoto, Kenji; Nishioka, Tomoki; Kaibuchi, Kozo; Takai, Satoko; Miyakawa, Tsuyoshi; Tanaka, Kohichi; Huda, Fathul; Hirai, Hirokazu; Hashimoto, Kouichi; Watanabe, Masahiko; Sakimura, Kenji; Kinoshita, Makoto.

In: Nature Communications, Vol. 6, 10090, 10.12.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance

AU - Ageta-Ishihara, Natsumi

AU - Yamazaki, Maya

AU - Konno, Kohtarou

AU - Nakayama, Hisako

AU - Abe, Manabu

AU - Hashimoto, Kenji

AU - Nishioka, Tomoki

AU - Kaibuchi, Kozo

AU - Takai, Satoko

AU - Miyakawa, Tsuyoshi

AU - Tanaka, Kohichi

AU - Huda, Fathul

AU - Hirai, Hirokazu

AU - Hashimoto, Kouichi

AU - Watanabe, Masahiko

AU - Sakimura, Kenji

AU - Kinoshita, Makoto

PY - 2015/12/10

Y1 - 2015/12/10

N2 - 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 (Î 3DGG) 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.

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Ageta-Ishihara N, Yamazaki M, Konno K, Nakayama H, Abe M, Hashimoto K et al. A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance. Nature Communications. 2015 Dec 10;6. 10090. https://doi.org/10.1038/ncomms10090