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Inhibition of NMDA Receptors Downregulates Astrocytic AQP4 to Suppress Seizures

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Abstract

Aquaporin 4 (AQP4), a water-specific channel protein locating on the astrocyte membrane, has been found to be antagonist, agonist and undergone closely related to epilepsy. Our previous study showed that inhibition of an N-methyl-d-aspartate receptor (NMDAR) subunit NR2A can suppress epileptic seizures, suggesting that AQP4 is potentially involved in NR2A-mediated epilepsy treatment. In this study, we aimed to explore the relevance of AQP4 in NR2A-mediated seizures treatment in pentylenetetrazol (PTZ)-induced rat models. We performed electroencephalogram (EEG) recording and examined AQP4 expression at mRNA and protein levels, and the downstream molecules of AQP4 as well. It showed that AQP4 expression was increased after the induction of seizures. Lateral ventricle pretreatment of NR2A inhibitor could mitigate the PTZ-induced seizures severity and counterbalance the increase of AQP4 expression. In contrast, NR2A activator that resulted in seizures aggravation could further augment the seizure-related elevations of AQP4 expression. Pharmacological inhibition of AQP4 alone could also suppress the PTZ-induced seizure activities, with decreased expressions of NF-κB p65, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α in the brain. The results indicated that increased expression of AQP4 might be an important mechanism involved in NR2A of NMDAR-mediated treatment for epileptic seizures, enlightening a potentially new target for seizures treatment.

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Acknowledgements

This work was supported by research grants from the National Natural Science Foundation of China (81771401, 81870992, 81870856, 81603681, U1603281), Natural Science Foundation of Guangdong Province of China (2020A1515010986), Science and Technology Planning Project of Guangdong Province of China (2017ZC0234), a technology project of Guangzhou (2018-1202-SF-0019).

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  1. Shuisheng Lei and Yan He have contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Key Laboratory of Neuroscience, School of Basic Medical Sciences, Department of Dermatology, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China

    Shuisheng Lei, Yan He, Ziting Zhu, Zhongrui Liu, Yuwan Lin, Yuehua He, Sheng Du, Pingyi Xu & Xiaoqin Zhu

  2. Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China

    Ziting Zhu, Yuwan Lin, Xiang Chen & Pingyi Xu

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  1. Shuisheng Lei
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  2. Yan He
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Contributions

All authors contributed to the study conception and design. SL, XZ, and PX designed the study. YH, ZZ, ZL, YL, YH, SD, and XC performed the research. XC analyzed the data. YH wrote the manuscript. XZ and PX revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Pingyi Xu or Xiaoqin Zhu.

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Lei, S., He, Y., Zhu, Z. et al. Inhibition of NMDA Receptors Downregulates Astrocytic AQP4 to Suppress Seizures. Cell Mol Neurobiol 40, 1283–1295 (2020). https://doi.org/10.1007/s10571-020-00813-6

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