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Astrocytic Kir4.1 channels and gap junctions account for spontaneous epileptic seizure

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  • Mengmeng Du
  • Jiajia Li
  • Liang Chen
  • Yuguo Yu
  • Ying Wu

Abstract

Experimental recordings in hippocampal slices indicate that astrocytic dysfunction may cause neuronal hyper-excitation or seizures. Considering that astrocytes play important roles in mediating local uptake and spatial buffering of K+ in the extracellular space of the cortical circuit, we constructed a novel model of an astrocyte-neuron network module consisting of a single compartment neuron and 4 surrounding connected astrocytes and including extracellular potassium dynamics. Next, we developed a new model function for the astrocyte gap junctions, connecting two astrocyte-neuron network modules. The function form and parameters of the gap junction were based on nonlinear regression fitting of a set of experimental data published in previous studies. Moreover, we have created numerical simulations using the above single astrocyte-neuron network module and the coupled astrocyte-neuron network modules. Our model validates previous experimental observations that both Kir4.1 channels and gap junctions play important roles in regulating the concentration of extracellular potassium. In addition, we also observe that changes in Kir4.1 channel conductance and gap junction strength induce spontaneous epileptic activity in the absence of external stimuli.Author summary: Astrocytes are critical regulators of normal physiological activity in the central nervous system, and one of their key functions is removing extracellular K+. In recent years, numerous biological studies have shown that astrocytic Kir4.1 channels and gap junctions between astrocytes act as major K+ clearance mechanisms. Dysfunction of either of these regulatory mechanisms may cause generation of K+-induced seizures. However, it is unclear how and to what extent these two K+-regulating processes lead to spontaneous epileptic activity. These questions were addressed in the present study by constructing novel single astrocyte-neuron network models and a coupled astrocyte-neuron module network connected by an astrocyte gap junction based on existing experimental observations and previous theoretical reports. Simulation results first verified that either down-regulation of astrocytic Kir4.1 channels or a decrease of the gap junction strength between astrocytes causes neuropathological hyper-excitability and spontaneous epileptic activity. These results imply that dysfunctional astrocytes should be considered as targets for therapeutic strategies in epilepsy.

Suggested Citation

  • Mengmeng Du & Jiajia Li & Liang Chen & Yuguo Yu & Ying Wu, 2018. "Astrocytic Kir4.1 channels and gap junctions account for spontaneous epileptic seizure," PLOS Computational Biology, Public Library of Science, vol. 14(3), pages 1-19, March.
  • Handle: RePEc:plo:pcbi00:1005877
    DOI: 10.1371/journal.pcbi.1005877
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    References listed on IDEAS

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    1. Ghanim Ullah & Steven J Schiff, 2010. "Assimilating Seizure Dynamics," PLOS Computational Biology, Public Library of Science, vol. 6(5), pages 1-12, May.
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    Cited by:

    1. Junli Zhao & Jinyi Sun & Yang Zheng & Yanrong Zheng & Yuying Shao & Yulan Li & Fan Fei & Cenglin Xu & Xiuxiu Liu & Shuang Wang & Yeping Ruan & Jinggen Liu & Shumin Duan & Zhong Chen & Yi Wang, 2022. "Activated astrocytes attenuate neocortical seizures in rodent models through driving Na+-K+-ATPase," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Ouyang, Zhicheng & Yu, Yangyang & Liu, Zhilong & Feng, PeiHua, 2023. "Transition of spatiotemporal patterns in neuron–astrocyte networks," Chaos, Solitons & Fractals, Elsevier, vol. 169(C).
    3. Li, Jiajia & Zhang, Xuan & Du, Mengmeng & Wu, Ying, 2022. "Switching behavior of the gamma power in the neuronal network modulated by the astrocytes," Chaos, Solitons & Fractals, Elsevier, vol. 159(C).
    4. Shen, Zhuan & Zhang, Honghui & Du, Lin & Deng, Zichen & Kurths, Jürgen, 2023. "Initiation and termination of epilepsy induced by Lévy noise: A view from the cortical neural mass model," Chaos, Solitons & Fractals, Elsevier, vol. 167(C).
    5. Zhao, Jinyi & Yu, Ying & Wang, Qingyun, 2022. "Dynamical regulation of epileptiform discharges caused by abnormal astrocyte function with optogenetic stimulation," Chaos, Solitons & Fractals, Elsevier, vol. 164(C).

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