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A sensitive and specific nanosensor for monitoring extracellular potassium levels in the brain

Nature Nanotechnology volume 15, pages 321–330 (2020)Cite this article

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Abstract

Extracellular potassium concentration affects the membrane potential of neurons, and, thus, neuronal activity. Indeed, alterations of potassium levels can be related to neurological disorders, such as epilepsy and Alzheimer’s disease, and, therefore, selectively detecting extracellular potassium would allow the monitoring of disease. However, currently available optical reporters are not capable of detecting small changes in potassium, in particular, in freely moving animals. Furthermore, they are susceptible to interference from sodium ions. Here, we report a highly sensitive and specific potassium nanosensor that can monitor potassium changes in the brain of freely moving mice undergoing epileptic seizures. An optical potassium indicator is embedded in mesoporous silica nanoparticles, which are shielded by an ultrathin layer of a potassium-permeable membrane, which prevents diffusion of other cations and allows the specific capturing of potassium ions. The shielded nanosensor enables the spatial mapping of potassium ion release in the hippocampus of freely moving mice.

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Fig. 1: Atom-level design and performance of the K+ nanosensors.
Fig. 2: Mechanistic studies on the high selectivity and sensitivity of the shielded nanosensors.
Fig. 3: Imaging of K+ release in cultured neurons.
Fig. 4: Imaging of K+ release in brain slices.
Fig. 5: Dynamic [K+]o fluctuations in the brain of freely moving mice.
Fig. 6: Multipoint [K+]o measurements in freely moving mice.

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Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The work done in the Korean institutions was mainly supported by the Institute for Basic Science of Korea (grant no. IBS-R006-D1). The work done in the Chinese institutions was mainly supported by the following funding programmes: the National Key Research and Development Programme of China (grant no. 2016YFA0203600), the National Natural Science Foundation of China (grant nos. 31822019, 51503180, 51611540345, 51703195, 81630098 and 91859116) and the One Belt and One Road International Cooperation Project from the Key Research and Development Programme of Zhejiang Province (grant no. 2019C04024). The work was also partly supported by the National Institute of Neurological Disorders and Stroke Research Project Grant (grant no. NS083402); the BioNano Health-Guard Research Center funded by the Ministry of Science and ICT of Korea as Global Frontier Project (grant no. H-GUARD_2013M3A6B2078947); the Basic Science Research Programme through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (grant no. NRF-2019R1F1A1060107); the Zhejiang Province Natural Science Foundation of China (grant no. LGF19C100002); and the Fundamental Research Funds for the Central Universities (grant nos. 2018QNA7020 and 2019QNA5001).

Author information

Author notes

  1. These authors contributed equally: Jianan Liu, Fangyuan Li, Yi Wang, Limin Pan.

Authors and Affiliations

  1. Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Republic of Korea

    Jianan Liu, Giho Ko, Kwangsoo Shin, Dokyoon Kim & Taeghwan Hyeon

  2. School of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea

    Jianan Liu, Giho Ko, Kwangsoo Shin & Taeghwan Hyeon

  3. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

    Fangyuan Li, Peihua Lin, Hongwei Liao, Yang Du, Zhong Chen & Daishun Ling

  4. Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Science, Zhejiang University, Hangzhou, China

    Fangyuan Li, Peihua Lin, Hongwei Liao, Yang Du & Daishun Ling

  5. Key Laboratory of Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, China

    Fangyuan Li & Daishun Ling

  6. Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China

    Yi Wang, Yanrong Zheng, Yingwei Xu, Fan Fei, Cenglin Xu & Zhong Chen

  7. Department of Chemistry, Seoul National University, Seoul, Republic of Korea

    Limin Pan & Jwa-Min Nam

  8. Department of Chemistry, Zhejiang University, Hangzhou, China

    Bo Zhang & Qi Wang

  9. Department of Bionano Engineering and Bionanotechnology, Hanyang University, Ansan, Republic of Korea

    Dokyoon Kim

  10. Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Sung-Soo Jang & Hee Jung Chung

  11. Center of Electron Microscope, State Key Laboratory of Silicon Material, School of Material Science and Engineering, Zhejiang University, Hangzhou, China

    He Tian

  12. CAS Key Laboratory of Bio-Inspired Materials and Interfacial Science, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, China

    Wei Guo

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  1. Jianan Liu
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Contributions

J.L. and D.L. conceived and designed the experiments. J.L. and L.P. fabricated K+ nanosensors. F.L., L.P., P.L., H.L., G.K., Y.D., K.S., D.K. and J.N. contributed to the nanosensor characterization and data analyses. H.T. carried out high-resolution TEM characterizations. B.Z. and Q.W. performed computer simulations. Y.W., Y.Z., Y.X., F.F., C.X. and S.J. performed in vitro and in vivo experiments and analyses. W.G. provided beneficial discussions to the sensing mechanism. All authors discussed the results and commented on the manuscript. J.L., F.L., Y.W., L.P., D.K., H.J.C., W.G., Z.C., T.H. and D.L. co-wrote the paper.

Corresponding authors

Correspondence to Zhong Chen, Taeghwan Hyeon or Daishun Ling.

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The authors declare no competing interests.

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Peer review information Nature Nanotechnology thanks Christophe Bernard and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–25

Reporting Summary

Supplementary Video 1

Results of molecular dynamics simulations showing the penetration of K+ through the filter membrane. Experiments were repeated five times independently.

Supplementary Video 2

Results of molecular dynamics simulations showing the exclusion of Na+ by the filter membrane. Experiments were repeated five times independently.

Supplementary Video 3

Behaviors of the freely moving normal mouse without epilepsy.

Supplementary Video 4

Behaviors of the epileptic mouse with seizure stage 1.

Supplementary Video 5

Behaviors of the epileptic mouse with seizure stage 2.

Supplementary Video 6

Behaviors of the epileptic mouse with seizure stage 3.

Supplementary Video 7

Behaviors of the epileptic mouse with seizure stage 4.

Supplementary Video 8

Behaviors of the epileptic mouse with seizure stage 5.

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Liu, J., Li, F., Wang, Y. et al. A sensitive and specific nanosensor for monitoring extracellular potassium levels in the brain. Nat. Nanotechnol. 15, 321–330 (2020). https://doi.org/10.1038/s41565-020-0634-4

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