title: A CDC42EP4/septin-based perisynaptic glial scaffold facilitates glutamate clearance.
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.
authors.affiliation: Division of Biological Sciences, Department of Molecular Biology, Nagoya University Graduate School of Science, Nagoya 464-8602, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Ageta-Ishihara
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Kohtarou
authors.initials: K
authors.lastname: Konno
authors.affiliation: Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8560, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nishioka
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8560, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.affiliation: Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Hattori
authors.affiliation: Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan.|Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
authors.forename: Tsuyoshi
authors.identifier: http://orcid.org/0000-0003-0137-8200
authors.initials: T
authors.lastname: Miyakawa
authors.affiliation: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Kohichi
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Fathul
authors.initials: F
authors.lastname: Huda
authors.affiliation: Department of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hirai
authors.affiliation: Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Division of Biological Sciences, Department of Molecular Biology, Nagoya University Graduate School of Science, Nagoya 464-8602, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D020555:GTP-Binding Protein Regulators / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016601:RNA-Binding Proteins; D058112:Septins / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins
chemical_list: C000607997:CDC42EP4 protein, mouse; D003598:Cytoskeletal Proteins; D027341:Excitatory Amino Acid Transporter 1; D020555:GTP-Binding Protein Regulators; D020690:GTPase-Activating Proteins; D016601:RNA-Binding Proteins; C493393:Slc1a3 protein, mouse; D018698:Glutamic Acid; D058112:Septins; D020741:rho GTP-Binding Proteins