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.

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Figure 1: EphA4 is required for LTP in postsynaptic CA1 cells.
Figure 2: Ephrin-A3 is required for TBS-induced LTP.
Figure 3: Upregulation of GLAST and GLT-1 protein levels in Epha4 mutants.
Figure 4: Astrocytic glutamate transporter currents.
Figure 5: Glutamate levels, postsynaptic responses to high frequency stimulation and pharmacological rescue of LTP.
Figure 6: Ephrin-A3 overexpression in astrocytes reduces glutamate transporters.
Figure 7: Ephrin-A3 overexpression in astrocytes increases susceptibility to excitotoxicity and seizures.

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Acknowledgements

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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A.F. designed, performed, analyzed most of the electrophysiology experiments and co-wrote the manuscript. S.P. designed, performed, analyzed the biochemical and quantitative anatomical studies and co-wrote the manuscript. S.D.H. and C.R.R. designed, performed and analyzed the astrocyte patch clamp recordings. M.A.C. and E.B.P. provided the Efna3−/− model, gave advice and aided in the interpretation of data. L.B., B.F. and T.K. performed and analyzed the induced seizure experiments. L.G. performed biochemical studies. Y.R. and R.S. provided the CA3-Cre mouse. K.K. provided Epha4lx/+ ES cells. R.K. supervised the project, designed experiments and co-wrote the manuscript. The two first authors, who contributed equally, are listed in alphabetical order.

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Correspondence to Sónia Paixão or Rüdiger Klein.

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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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