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Nat Commun. 2015 Dec 10;6:10090. doi: 10.1038/ncomms10090.

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

Author information

1
Division of Biological Sciences, Department of Molecular Biology, Nagoya University Graduate School of Science, Nagoya 464-8602, Japan.
2
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
3
Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
4
Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
5
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
6
Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8560, Japan.
7
Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan.
8
Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
9
Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
10
Department of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.

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.

PMID:
26657011
PMCID:
PMC4682051
DOI:
10.1038/ncomms10090
[Indexed for MEDLINE]
Free PMC Article

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