title: Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport.
abstract: 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.
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, Martinsried, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Filosa
authors.forename: Sónia
authors.initials: S
authors.lastname: Paixão
authors.forename: Silke D
authors.initials: SD
authors.lastname: Honsek
authors.forename: Maria A
authors.initials: MA
authors.lastname: Carmona
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.forename: Berend
authors.initials: B
authors.lastname: Feddersen
authors.forename: Louise
authors.initials: L
authors.lastname: Gaitanos
authors.forename: York
authors.initials: Y
authors.lastname: Rudhard
authors.forename: Ralf
authors.initials: R
authors.lastname: Schoepfer
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Klas
authors.initials: K
authors.lastname: Kullander
authors.forename: Christine R
authors.initials: CR
authors.lastname: Rose
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klein
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001703:Biophysics; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D036384:Ephrin-A3 / Q000235:genetics / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D017774:Long-Term Potentiation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques / Q000379:methods; D010433:Pentylenetetrazole; D036122:Receptor, EphA4 / Q000172:deficiency / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
chemical_list: C508240:(2S,3S)-3-(3-(4-(trifluoromethyl)benzoylamino)benzyloxy)aspartate; D036384:Ephrin-A3; D018691:Excitatory Amino Acid Antagonists; D027341:Excitatory Amino Acid Transporter 1; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins; D001224:Aspartic Acid; D018698:Glutamic Acid; D036122:Receptor, EphA4; D010433:Pentylenetetrazole