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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebellum / cytology
  • Cerebellum / metabolism
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Excitatory Amino Acid Transporter 1 / genetics
  • Excitatory Amino Acid Transporter 1 / metabolism
  • GTP-Binding Protein Regulators / genetics
  • GTP-Binding Protein Regulators / metabolism*
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Gene Expression Regulation / physiology
  • Glutamic Acid / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Neuroglia / metabolism*
  • Neurons / cytology
  • Neurons / metabolism
  • Septins / genetics
  • Septins / metabolism*

Substances

  • CDC42EP4 protein, mouse
  • Cytoskeletal Proteins
  • Excitatory Amino Acid Transporter 1
  • GTP-Binding Protein Regulators
  • GTPase-Activating Proteins
  • Slc1a3 protein, mouse
  • Glutamic Acid
  • Septins