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Chemokine CCL2 enhances NMDA receptor-mediated excitatory postsynaptic current in rat hippocampal slices-a potential mechanism for HIV-1-associated neuropathy?

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Abstract

Human immunodeficiency virus type 1 (HIV-1)-infected mononuclear phagocytes (brain macrophages and microglial cells) release proinflammatory cytokines and chemokines. Elevated levels of chemokine CC motif ligand 2 (CCL2, known previously as monocyte chemoattractant protein-1) have been detected in serum and cerebrospinal fluid (CSF) of HIV-1-infected individuals and the raised CCL2 in the CSF correlates with HIV-1-associated neurocognitive disorders. To understand how elevated CCL2 induces HIV-1-associated neuropathy, we studied effects of CCL2 on excitatory postsynaptic current (EPSCs) in the CA1 region of rat hippocampal brain slices using whole-cell patch recording techniques. The AMPA receptor (AMPAR)-mediated EPSC (EPSCAMPAR) and N-Methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated EPSCs (EPSCNMDAR) were isolated pharmacologically. Bath application of CCL2 produced a significant enhancement of the amplitudes of EPSCs, EPSCAMPAR and EPSCNMDAR. Further studies revealed that CCL2 potentiated NMDAR subtype NR2A-mediated EPSC (EPSCNR2AR) and NR2B-mediated EPSC (EPSCNR2BR). To determine the site of action, we recorded spontaneous mini EPSCs (mEPSC) before and during bath application of CCL2. Our results showed that CCL2 decreased inter event interval (IEI) and increased the frequency of mEPSCs without change on the amplitude, suggesting a presynaptic site of CCL2 action. CCL2 was also found to injure primary rat hippocampal neuronal cultures and neuronal dendrites in the CA1 region of hippocampal slices. The CCL2-associated neuronal and dendritic injuries were blocked by a specific NMDAR antagonist or by a CCR2 receptor antagonist, indicating that CCL2-associated neural injury was mediated via NMDARs and/or CCR2 receptors. Taken together, these results suggest a potential role CCL2 may play in HIV-1-associated neuropathology.

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Acknowledgments

This work was supported by NIH grant R01 NS063878, R01 NS077873 (HX), the National Natural Science Foundation of China 81360192 (YZ), Guangxi Natural Science Foundation 2012GXNSFCA053004 (YZ), Guangxi Education Department Foundation 201203YB041 (YZ).

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  1. Hongmei Tang

    Present address: Department of Pathophysiology, Ji-nan University, Guangzhou, 510632, China

Authors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    Yan Zhou, Hongmei Tang & Huangui Xiong

  2. Department of Pharmacology, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China, 530021

    Yan Zhou

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Correspondence to Yan Zhou or Huangui Xiong.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of University of Nebraska Medical Center, Omaha, NE, USA.

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The authors declare that they have no competing interests.

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Zhou, Y., Tang, H. & Xiong, H. Chemokine CCL2 enhances NMDA receptor-mediated excitatory postsynaptic current in rat hippocampal slices-a potential mechanism for HIV-1-associated neuropathy?. J Neuroimmune Pharmacol 11, 306–315 (2016). https://doi.org/10.1007/s11481-016-9660-2

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