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The Ephrin-A5/EphA4 Interaction Modulates Neurogenesis and Angiogenesis by the p-Akt and p-ERK Pathways in a Mouse Model of TLE

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Abstract

Studies have shown that neurogenesis and angiogenesis do exist in temporal lobe epilepsy (TLE). The ephrin ligands and Eph receptors are the largest members of receptor tyrosine kinases, and their interaction via cell–cell contact participates in cell proliferation, differentiation, migration, and tissue remodeling. However, there is little information about the function of the ephrin-A5/EphA4 complex in TLE. In the current study, we found that ephrin-A5 was expressed in astrocytes, while EphA4 existed in endothelial cells in the hippocampus in a mouse model of TLE. Furthermore, the messenger RNA (mRNA) and protein levels of both ephrin-A5 and EphA4 and the binding capacity of ephrin-A5/EphA4 showed gradual increase in spatiotemporal course. When ephrin-A5-Fc was injected into the hippocampus at 3 days post-status epilepticus (SE) for 7 days, the spontaneous recurrent seizure (SRS) frequency and intensity of the mice attenuated in the following 2 weeks. Furthermore, doublecortin-positive neuronal progenitor cells were reduced in the subgranular zone, and the density of microvessels decreased in the hilus. The molecular mechanism was attributed to ephrin-A5-Fc-induced inhibition of phosphorylated ERK (p-ERK) and phosphorylated Akt (p-Akt), and also EphA4 and VEGF reduction. In summary, interaction between ephrin-A5 and EphA4 could mediate the ERK and Akt signaling pathways in pilocarpine-induced epilepsy, and intervention of the ephrin/Eph interaction may play an essential role in the suppression of newborn neuron generation, microvessel remodeling, and SRS in a mouse model of TLE. The ephrin-A5/EphA4 communication may provide a potential therapy for the treatment of TLE.

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Acknowledgments

This study is supported by the National Natural Science Foundation of China (81100967; 81301160) and Specialized Research Fund for the Doctoral Program of Higher Education (20110162120002). We would like to thank Jinghui Liang for tissue preparation and thank Zhaohui Luo and Zhiguo Wu for outstanding technical assistance with co-immunoprecipitation and confocal microscopy.

Conflict of Interest

There is no conflict of interest among the authors.

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Authors and Affiliations

  1. Department of Neurology, Xiangya Hospital, Central South University, Hunan, 410008, China

    Yi Shu, Bo Xiao, Qian Wu, Tiantian Liu, Yang Du, Si Chen, Li Feng, Lili Long & Yi Li

  2. Department of Neurology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01604, USA

    Yi Li

  3. Department of Radiology, Xiangya Hospital, Central South University, Hunan, 410008, China

    Haiyun Tang

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  1. Yi Shu
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  2. Bo Xiao
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Shu, Y., Xiao, B., Wu, Q. et al. The Ephrin-A5/EphA4 Interaction Modulates Neurogenesis and Angiogenesis by the p-Akt and p-ERK Pathways in a Mouse Model of TLE. Mol Neurobiol 53, 561–576 (2016). https://doi.org/10.1007/s12035-014-9020-2

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