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.
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We thank M. Bösl and the transgenic core facility for generating transgenic mice; E. Kandel (Columbia University) and F. Kirchhoff (Max Planck Institute of Experimental Medicine, Göttingen) for transgenic mice; M. Klein and O. Gökce for technical help; K. Deininger, C. Erlacher, V. Staiger, V. Stein and M. Traut for scientific input and suggestions; M. Korte, I. Kadow, V. Stein, J. Egea and R. Fonseca for critical comments on the manuscript. S.P. was supported by a postdoctoral fellowship from Fundação para a Ciência e Tecnologia of Portugal, co-funded by Programa Operacional Ciência e Inovação 2010 and Fundo Social Europeu. M.A.C. was supported by a fellowship from Fundación Española para la Ciencia y la Tecnología. This work was in part supported by grants from the European Union (Endotrack), the Deutsche Forschungsgemeinschaft (SPP1172) and the Max-Planck Society (all to R.K.), the Wellcome Trust and the Biotechnology and Biological Sciences Research Council, UK (R.S.), the German National Genome Research Network (NGF N grant 01GR0430) (T.K.), and US National Institutes of Health grant HD025938 (E.B.P.).
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Filosa, A., Paixão, S., Honsek, S. et al. Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nat Neurosci 12, 1285–1292 (2009). https://doi.org/10.1038/nn.2394
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