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Neuroligin-1 Knockdown Suppresses Seizure Activity by Regulating Neuronal Hyperexcitability

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Abstract

Abnormally synchronized synaptic transmission in the brain leads to epilepsy. Neuroligin-1 (NL1) is a synaptic cell adhesion molecule localized at excitatory synapses. NL1 modulates synaptic transmission and determines the properties of neuronal networks in the mammalian central nervous system. We showed that the expression of NL1 and its binding partner neurexin-1β was increased in temporal lobe epileptic foci in patients and lithium-pilocarpine-treated epileptic rats. We investigated electrophysiological and behavioral changes in epileptic rats after lentivirally mediated NL1 knockdown in the hippocampus to determine whether NL1 suppression prevented seizures and, if so, to explore the probable underlying mechanisms. Our behavioral studies revealed that NL1 knockdown in epileptic rats reduced seizure severity and increased seizure latency. Whole-cell patch-clamp recordings of CA1 pyramidal neurons in hippocampal slices from NL1 knockdown epileptic rats revealed a decrease in spontaneous action potential frequency and a decrease in miniature excitatory postsynaptic current (mEPSC) frequency but not amplitude. The amplitude of N-methyl-d-aspartate receptor (NMDAR)-dependent EPSCs was also selectively decreased. Notably, NL1 knockdown reduced total NMDAR1 expression and the surface/total ratio in the hippocampus of epileptic rats. Taken together, these data indicate that NL1 knockdown in epileptic rats may reduce the frequency and severity of seizures and suppress neuronal hyperexcitability via changes in postsynaptic NMDARs.

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Acknowledgments

This work was supported by National Natural Science Foundation Of China (grant numbers are 81401070, 81471319, and 81301630). The authors sincerely thank the patients and their families for their participation in this study. We thank the Xinqiao Hospital of the Third Military Medical University, Beijing Tiantan Hospital and Xuanwu Hospital of the Capital University of Medical Sciences for their support in brain tissue procurement, and the National Institutes of Health of China and the Ethics Committee on Human Research of the Chongqing Medical University.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Emergency and Intensive Care Unit, The First Affiliated Hospital of Chongqing Medical University, 1 You Yi Road, Chongqing, 400016, China

    Min Fang

  2. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, 1 You Yi Road, Chongqing, 400016, China

    Jin-Lai Wei

  3. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 You Yi Road, Chongqing, 400016, China

    Bo Tang, Jing Liu, Ling Chen, Jing Luo, Guo-Jun Chen & Xue-Feng Wang

  4. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, 1 You Yi Road, Chongqing, 400016, China

    Zhao-Hua Tang

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  1. Min Fang
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Fang, M., Wei, JL., Tang, B. et al. Neuroligin-1 Knockdown Suppresses Seizure Activity by Regulating Neuronal Hyperexcitability. Mol Neurobiol 53, 270–284 (2016). https://doi.org/10.1007/s12035-014-8999-8

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