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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Aspartic Acid / analogs & derivatives
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Aspartic Acid / pharmacology
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Biophysics
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Disease Models, Animal
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Electric Stimulation / methods
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Ephrin-A3 / genetics
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Ephrin-A3 / metabolism*
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Amino Acid Transporter 1 / metabolism
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Excitatory Postsynaptic Potentials / genetics
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Glial Fibrillary Acidic Protein / metabolism
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Glutamic Acid / metabolism*
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Green Fluorescent Proteins / genetics
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Hippocampus / cytology
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Long-Term Potentiation / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neuroglia / physiology*
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Neurons / physiology*
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Organ Culture Techniques
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Patch-Clamp Techniques / methods
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Pentylenetetrazole
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Receptor, EphA4 / deficiency
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Receptor, EphA4 / metabolism*
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Seizures / chemically induced
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Seizures / genetics
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Seizures / physiopathology
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Signal Transduction / physiology
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Synapses / physiology
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Up-Regulation / genetics
Substances
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(2S,3S)-3-(3-(4-(trifluoromethyl)benzoylamino)benzyloxy)aspartate
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Ephrin-A3
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Excitatory Amino Acid Antagonists
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Excitatory Amino Acid Transporter 1
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Glial Fibrillary Acidic Protein
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Green Fluorescent Proteins
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Aspartic Acid
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Glutamic Acid
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Receptor, EphA4
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Pentylenetetrazole