CXCR7 regulates epileptic seizures by controlling the synaptic activity of hippocampal granule cells

Tao Xu,Ying Liu,Xinyuan Yu,Yangmei Chen,Changhong Tan,Juan Yang,Shu Ou,Jing Deng,Jinxian Yuan,Teng Wang,Xi Liu

doi:10.1038/s41419-019-2052-9

Abstract

C–X–C motif chemokine receptor 7 (CXCR7), which mediates the immune response in the brain, was recently reported to regulate neurological functions. However, the role of CXCR7 in epilepsy remains unclear. Here, we found that CXCR7 was upregulated in the hippocampal dentate gyrus (DG) of mice subjected to kainic acid (KA)-induced epilepsy and in the brain tissues of patients with temporal lobe epilepsy. Silencing CXCR7 in the hippocampal DG region exerted an antiepileptic effect on the KA-induced mouse model of epilepsy, whereas CXCR7 overexpression produced a seizure-aggravating effect. Mechanistically, CXCR7 selectively regulated N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic neurotransmission in hippocampal dentate granule cells by modulating the cell membrane expression of the NMDAR subunit2A, which requires the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Thus, CXCR7 may regulate epileptic seizures and represents a novel target for antiepileptic treatments.

Highlights

Epilepsy is a chronic and serious neurological disease with diverse clinical manifestations[1]
C–X–C motif chemokine receptor 7 (CXCR7) was colocalized with the neuronal marker neuron-specific enolase (NSE) (Fig. 1d), indicating that CXCR7 was expressed in hippocampal dentate granule cells (GCs)
The second innovative finding is the alteration in the epileptic phenotype: decreased CXCR7 expression in the hippocampal dentate gyrus (DG) exerts a beneficial effect on controlling epileptic seizures, whereas increased CXCR7 expression promotes epileptic seizures

Summary

Introduction

Epilepsy is a chronic and serious neurological disease with diverse clinical manifestations[1]. Recent studies have investigated the underlying mechanism of epilepsy, its etiology remains largely unclear and deserves further investigation, which may improve therapeutic efficacy of epilepsy treatments and enable the development of more effective preventive and therapeutic strategies. Chemokines and their specific chemokine receptors are known to participate in immune pathways in the brain that play a crucial role in regulating brain function and behavior[4,5]. C–X–C motif chemokine ligand 12 (CXCL12, known as stromal cell-derived factor 1, or SDF-1) is a key chemokine that regulates the immune response in the brain[6,7].

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