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Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport.

Astrocytes are critical participants in synapse development and function, but their role in synaptic plasticity is unclear. Eph receptors and their ephrin ligands have been suggested to regulate neuron-glia interactions, and EphA4-mediated ephrin reverse signaling is required for synaptic plasticity in the hippocampus. Here we show that long-term potentiation (LTP) at the CA3-CA1 synapse is modulated by EphA4 in the postsynaptic CA1 cell and by ephrin-A3, a ligand of EphA4 that is found in astrocytes. Lack of EphA4 increased the abundance of glial glutamate transporters, and ephrin-A3 modulated transporter currents in astrocytes. Pharmacological inhibition of glial glutamate transporters rescued the LTP defects in EphA4 (Epha4) and ephrin-A3 (Efna3) mutant mice. Transgenic overexpression of ephrin-A3 in astrocytes reduces glutamate transporter levels and produces focal dendritic swellings possibly caused by glutamate excitotoxicity. These results suggest that EphA4/ephrin-A3 signaling is a critical mechanism for astrocytes to regulate synaptic function and plasticity.

Pubmed ID: 19734893


  • Filosa A
  • Paix√£o S
  • Honsek SD
  • Carmona MA
  • Becker L
  • Feddersen B
  • Gaitanos L
  • Rudhard Y
  • Schoepfer R
  • Klopstock T
  • Kullander K
  • Rose CR
  • Pasquale EB
  • Klein R


Nature neuroscience

Publication Data

October 28, 2009

Associated Grants

  • Agency: NICHD NIH HHS, Id: HD025938
  • Agency: NICHD NIH HHS, Id: P01 HD025938
  • Agency: Biotechnology and Biological Sciences Research Council, Id:
  • Agency: Wellcome Trust, Id:

Mesh Terms

  • Animals
  • Animals, Newborn
  • Aspartic Acid
  • Biophysics
  • Disease Models, Animal
  • Electric Stimulation
  • Ephrin-A3
  • Excitatory Amino Acid Antagonists
  • Excitatory Amino Acid Transporter 1
  • Excitatory Postsynaptic Potentials
  • Glial Fibrillary Acidic Protein
  • Glutamic Acid
  • Green Fluorescent Proteins
  • Hippocampus
  • Long-Term Potentiation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuroglia
  • Neurons
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Pentylenetetrazole
  • Receptor, EphA4
  • Seizures
  • Signal Transduction
  • Synapses
  • Up-Regulation