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


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.


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



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.


  1. 1.
    Talley EM, Solorzano G, Lei Q, Kim D, Bayliss DA (2001) CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. J Neurosci 21(19):7491–7505CrossRefGoogle Scholar
  2. 2.
    de la Pena E, Malkia A, Vara H, Caires R, Ballesta JJ, Belmonte C, Viana F (2012) The influence of cold temperature on cellular excitability of hippocampal networks. PLoS One 7(12):e52475. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Enyedi P, Czirjak G (2010) Molecular background of leak K+ currents: two-pore domain potassium channels. Physiol Rev 90(2):559–605. CrossRefPubMedGoogle Scholar
  4. 4.
    Honore E (2007) The neuronal background K2P channels: focus on TREK1. Nat Rev Neurosci 8(4):251–261. CrossRefPubMedGoogle Scholar
  5. 5.
    Feliciangeli S, Chatelain FC, Bichet D, Lesage F (2015) The family of K2P channels: salient structural and functional properties. J Physiol 593(12):2587–2603. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Westphalen RI, Krivitski M, Amarosa A, Guy N, Hemmings HC Jr (2007) Reduced inhibition of cortical glutamate and GABA release by halothane in mice lacking the K+ channel, TREK-1. Br J Pharmacol 152(6):939–945. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Sandoz G, Levitz J, Kramer RH, Isacoff EY (2012) Optical control of endogenous proteins with a photoswitchable conditional subunit reveals a role for TREK1 in GABA(B) signaling. Neuron 74(6):1005–1014. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Heurteaux C, Lucas G, Guy N, El Yacoubi M, Thummler S, Peng XD, Noble F, Blondeau N et al (2006) Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci 9(9):1134–1141. CrossRefPubMedGoogle Scholar
  9. 9.
    Weng W, Chen Y, Wang M, Zhuang Y, Behnisch T (2016) Potentiation of Schaffer-collateral CA1 synaptic transmission by eEF2K and p38 MAPK mediated mechanisms. Front Cell Neurosci 10:247. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mirkovic K, Palmersheim J, Lesage F, Wickman K (2012) Behavioral characterization of mice lacking Trek channels. Front Behav Neurosci 6:60. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang-Lazdunski L, Widmann C et al (2004) TREK-1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J 23(13):2684–2695. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Cai Y, Peng Z, Guo H, Wang F, Zeng Y (2017) TREK-1 pathway mediates isoflurane-induced memory impairment in middle-aged mice. Neurobiol Learn Mem 145:199–204. CrossRefPubMedGoogle Scholar
  13. 13.
    Namiranian K, Lloyd EE, Crossland RF, Marrelli SP, Taffet GE, Reddy AK, Hartley CJ, Bryan RM Jr (2010) Cerebrovascular responses in mice deficient in the potassium channel, TREK-1. Am J Physiol Regul Integr Comp Physiol 299(2):R461–R469. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhong S, Du Y, Kiyoshi CM, Ma B, Alford CC, Wang Q, Yang Y, Liu X et al (2016) Electrophysiological behavior of neonatal astrocytes in hippocampal stratum radiatum. Mol Brain 9:34. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Du Y, Kiyoshi CM, Wang Q, Wang W, Ma B, Alford CC, Zhong S, Wan Q et al (2016) Genetic deletion of TREK-1 or TWIK-1/TREK-1 potassium channels does not alter the basic electrophysiological properties of mature hippocampal astrocytes in situ. Front Cell Neurosci 10:13. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wang W, Putra A, Schools GP, Ma B, Chen H, Kaczmarek LK, Barhanin J, Lesage F et al (2013) The contribution of TWIK-1 channels to astrocyte K(+) current is limited by retention in intracellular compartments. Front Cell Neurosci 7:246. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Pannasch U, Vargova L, Reingruber J, Ezan P, Holcman D, Giaume C, Sykova E, Rouach N (2011) Astroglial networks scale synaptic activity and plasticity. Proc Natl Acad Sci U S A 108(20):8467–8472. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Zhou M, Xu G, Xie M, Zhang X, Schools GP, Ma L, Kimelberg HK, Chen H (2009) TWIK-1 and TREK-1 are potassium channels contributing significantly to astrocyte passive conductance in rat hippocampal slices. J Neurosci 29(26):8551–8564. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wang W, Kiyoshi CM, Du Y, Ma B, Alford CC, Chen H, Zhou M (2016) mGluR3 activation recruits cytoplasmic TWIK-1 channels to membrane that enhances ammonium uptake in hippocampal astrocytes. Mol Neurobiol 53(9):6169–6182. CrossRefPubMedGoogle Scholar
  20. 20.
    Ferreira TA, Blackman AV, Oyrer J, Jayabal S, Chung AJ, Watt AJ, Sjostrom PJ, van Meyel DJ (2014) Neuronal morphometry directly from bitmap images. Nat Methods 11(10):982–984. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    McKinney RA (2010) Excitatory amino acid involvement in dendritic spine formation, maintenance and remodelling. J Physiol 588(Pt 1):107–116. CrossRefPubMedGoogle Scholar
  22. 22.
    Leger M, Quiedeville A, Bouet V, Haelewyn B, Boulouard M, Schumann-Bard P, Freret T (2013) Object recognition test in mice. Nat Protoc 8(12):2531–2537. CrossRefPubMedGoogle Scholar
  23. 23.
    Hille B (2001) Ion channels of excitable cells. Sinauer, Sunderland, MAGoogle Scholar
  24. 24.
    Devader C, Khayachi A, Veyssiere J, Moha O, Maati H, Roulot M, Moreno S, Borsotto M et al (2015) In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin. Br J Pharmacol 172(10):2604–2617. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kerchner GA, Nicoll RA (2008) Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat Rev Neurosci 9(11):813–825. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Liao D, Hessler NA, Malinow R (1995) Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature 375(6530):400–404. CrossRefPubMedGoogle Scholar
  27. 27.
    Olsen ML, Khakh BS, Skatchkov SN, Zhou M, Lee CJ, Rouach N (2015) New insights on astrocyte ion channels: critical for homeostasis and neuron-glia signaling. J Neurosci 35(41):13827–13835. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ma B, Buckalew R, Du Y, Kiyoshi CM, Alford CC, Wang W, McTigue DM, Enyeart JJ et al (2016) Gap junction coupling confers isopotentiality on astrocyte syncytium. Glia 64(2):214–226. CrossRefPubMedGoogle Scholar
  29. 29.
    Kiyoshi CM, Du Y, Zhong S, Wang W, Taylor AT, Xiong B, Ma B, Terman D et al (2018) Syncytial isopotentiality: a system-wide electrical feature of astrocytic networks in the brain. Glia 66(12):2756–2769. CrossRefPubMedGoogle Scholar
  30. 30.
    Hocking JC, Pollock NS, Johnston J, Wilson RJ, Shankar A, McFarlane S (2012) Neural activity and branching of embryonic retinal ganglion cell dendrites. Mech Dev 129(5-8):125–135. CrossRefPubMedGoogle Scholar
  31. 31.
    Frangeul L, Kehayas V, Sanchez-Mut JV, Fievre S, Krishna KK, Pouchelon G, Telley L, Bellone C et al (2017) Input-dependent regulation of excitability controls dendritic maturation in somatosensory thalamocortical neurons. Nat Commun 8(1):2015. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H (2003) Structure-stability-function relationships of dendritic spines. Trends Neurosci 26(7):360–368. CrossRefPubMedGoogle Scholar
  33. 33.
    Unudurthi SD, Wu X, Qian L, Amari F, Onal B, Li N, Makara MA, Smith SA et al (2016) Two-pore K+ channel TREK-1 regulates sinoatrial node membrane excitability. J Am Heart Assoc 5(4):e002865. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yuste R, Bonhoeffer T (2001) Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 24:1071–1089. CrossRefPubMedGoogle Scholar
  35. 35.
    Zhou YD, Lee S, Jin Z, Wright M, Smith SE, Anderson MP (2009) Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy. Nat Med 15(10):1208–1214. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ (2011) Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cerebr Blood Flow Metab 31(1):17–35. CrossRefGoogle Scholar
  37. 37.
    Geiger JR, Jonas P (2000) Dynamic control of presynaptic Ca(2+) inflow by fast-inactivating K(+) channels in hippocampal mossy fiber boutons. Neuron 28(3):927–939CrossRefGoogle Scholar
  38. 38.
    Yang CT, Lu GL, Hsu SF, MacDonald I, Chiou LC, Hung SY, Chen YH (2018) Paeonol promotes hippocampal synaptic transmission: the role of the Kv2.1 potassium channel. Eur J Pharmacol 827:227–237. CrossRefPubMedGoogle Scholar
  39. 39.
    Gu J, Lee CW, Fan Y, Komlos D, Tang X, Sun C, Yu K, Hartzell HC et al (2010) ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. Nat Neurosci 13(10):1208–1215. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Malik R, Johnston D (2017) Dendritic GIRK channels gate the integration window, plateau potentials, and induction of synaptic plasticity in dorsal but not ventral CA1 neurons. J Neurosci 37(14):3940–3955. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Turrigiano GG (2017) The dialectic of Hebb and homeostasis. Philos Trans R Soc Lond Ser B Biol Sci 372(1715). CrossRefGoogle Scholar
  42. 42.
    Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28(1):264–278. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Gilbert TH, McNamara RK, Corcoran ME (1996) Kindling of hippocampal field CA1 impairs spatial learning and retention in the Morris water maze. Behav Brain Res 82(1):57–66CrossRefGoogle Scholar
  44. 44.
    Zhang X, Zheng Y, Ren Q, Zhou H (2017) The involvement of potassium channel ORK1 in short-term memory and sleep in Drosophila. Medicine 96(27):e7299. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Zuckerman H, Pan Z, Park C, Brietzke E, Musial N, Shariq AS, Iacobucci M, Yim SJ et al (2018) Recognition and treatment of cognitive dysfunction in major depressive disorder. Front Psychiatry 9:655. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Djillani A, Pietri M, Mazella J, Heurteaux C, Borsotto M (2019) Fighting against depression with TREK-1 blockers: past and future. A focus on spadin Pharmacology & Therapeutics 194:185-198. doi: CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

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

Personalised recommendations