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TREK-1 Null Impairs Neuronal Excitability, Synaptic Plasticity, and Cognitive Function

  • Wei Wang
  • Conrad M. Kiyoshi
  • Yixing Du
  • Anne T. Taylor
  • Erica R. Sheehan
  • Xiao Wu
  • Min ZhouEmail author
Article

Abstract

TREK-1, a two-pore-domain K+ channel, is highly expressed in the central nervous system. Although aberrant expression of TREK-1 is implicated in cognitive impairment, the cellular and functional mechanism underlying this channelopathy is poorly understood. Here we examined TREK-1 contribution to neuronal morphology, excitability, synaptic plasticity, and cognitive function in mice deficient in TREK-1 expression. TREK-1 immunostaining signal mainly appeared in hippocampal pyramidal neurons, but not in astrocytes. TREK-1 gene knockout (TREK-1 KO) increases dendritic sprouting and the number of immature spines in hippocampal CA1 pyramidal neurons. Functionally, TREK-1 KO increases neuronal excitability and enhances excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs). The increased EPSCs appear to be attributed to an increased release probability of presynaptic glutamate and functional expression of postsynaptic AMPA receptors. TREK-1 KO decreased the paired-pulse ratio and severely occluded the long-term potentiation (LTP) in the CA1 region. These altered synaptic transmission and plasticity are associated with recognition memory deficit in TREK-1 KO mice. Although astrocytic expression of TREK-1 has been reported in previous studies, TREK-1 KO does not alter astrocyte membrane K+ conductance or the syncytial network function in terms of syncytial isopotentiality. Altogether, TREK-1 KO profoundly affects the cellular structure and function of hippocampal pyramidal neurons. Thus, the impaired cognitive function in diseases associated with aberrant expression of TREK-1 should be attributed to the failure of this K+ channel in regulating neuronal morphology, excitability, synaptic transmission, and plasticity.

Keywords

TREK-1 (tandem of pore domain in a weak inwardly rectifying K+ channel (Twik)-related K+ channels) Hippocampus Synaptic transmission Synaptic plasticity Cognitive impairment 

Notes

Acknowledgments

The authors thank Dr. Fangli Zhao for assisting the field potential recording.

Author Contributions

WW and MZ conceived the project. WW, CMK, YD, AT, and XW conducted the research or assisted the research, discussed the project, and assisted the manuscript preparation. WW and MZ wrote the manuscript. MZ supervised the project. All authors are accountable for all aspects of the work and all persons designated as authors qualify for the authorship, and all those who qualify for authorship are listed. All authors read and approved the final version of the manuscript submitted for publication.

Funding Information

This work was sponsored by grants from the National Institute of Neurological Disorders and Stroke R56NS097972 and RO1NS062784 (MZ), and P30NS104177 (to Dr. Candice Askwith). WW was supported by grants from the National Natural Science Foundation of China (No. 81400973) and the Fundamental Research Funds for the Central Universities of China, HUST (2018KFYYXJJ081).

Compliance with Ethical Standards

All procedures performed in studies involving animals were in accordance with a protocol approved by the Animal Care and Use Committees of The Ohio State University and all efforts were made to minimize suffering. This article does not contain any studies with human participants performed by any of the authors.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 1.Department of NeuroscienceOhio State University Wexner Medical CenterColumbusUSA
  2. 2.Department of Physiology, School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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