Organic electrochemical transistor arrays for real-time mapping of evoked neurotransmitter release in vivo

  1. Kai Xie
  2. Naixiang Wang
  3. Xudong Lin
  4. Zixun Wang
  5. Xi Zhao
  6. Peilin Fang
  7. Haibing Yue
  8. Junhwi Kim
  9. Jing Luo
  10. Shaoyang Cui
  11. Feng Yan  Is a corresponding author
  12. Peng Shi  Is a corresponding author
  1. City University of Hong Kong, China
  2. The Hong Kong Polytechnic University, Hong Kong
  3. City University of Hong Kong, Hong Kong
  4. Shenzhen Hospital of Guangzhou University of Chinese Medicine, China

Abstract

Though neurotransmitters are essential in neural signal transmission, techniques for in vivo analysis are still limited. Here, we describe an organic electrochemical transistor array (OECT-array) technique for monitoring catecholamine neurotransmitters (CA-NTs) in rat brains. The OECT-array is an active sensor with intrinsic amplification capability, allowing real-time and direct readout of transient CA-NT release with a sensitivity of nanomolar range and a temporal resolution of several milliseconds. The device has a working voltage lower than half of that typically used in a prevalent cyclic voltammetry measurement, and operates continuously in vivo for hours without significant signal drift, which is inaccessible for existing methods. With the OECT-array, we demonstrate simultaneous mapping of evoked dopamine release at multiple striatal brain regions in different physiological scenarios, and reveal a complex cross-talk between mesolimbic and nigrostriatal pathways, which is heterogeneously affected by the reciprocal innervation between ventral tegmental area and substantia nigra pars compacta.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided as supplementary files.

Article and author information

Author details

  1. Kai Xie

    Department of Biomedical Engineering, City University of Hong Kong, Kowloon, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Naixiang Wang

    Department of Applied Physics, The Hong Kong Polytechnic University, Hong Kong, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  3. Xudong Lin

    Department of Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  4. Zixun Wang

    Department of Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  5. Xi Zhao

    Department of Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  6. Peilin Fang

    Department of Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  7. Haibing Yue

    Department of Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  8. Junhwi Kim

    Department of Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.
  9. Jing Luo

    Department of Rehabilitation, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Shaoyang Cui

    Department of Rehabilitation, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Feng Yan

    Department of Applied Physics, The Hong Kong Polytechnic University, Hong Kong, Hong Kong
    For correspondence
    apafyan@polyu.edu.hk
    Competing interests
    The authors declare that no competing interests exist.
  12. Peng Shi

    Department of Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong
    For correspondence
    pengshi@cityu.edu.hk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0629-4161

Funding

General Research Funds (11278616)

  • Peng Shi

General Research Funds (11218015)

  • Peng Shi

General Research Funds (11203017)

  • Peng Shi

Health and Medical Research Fund (06172336)

  • Peng Shi

Collaborative Research Funds (C5015-15G)

  • Feng Yan
  • Peng Shi

The funders provided resources for the study design, data collection, and interpretation.

Reviewing Editor

  1. Mehmet Fatih Yanik, Massachusetts Institute of Technology, United States

Ethics

Animal experimentation: All experimental procedures involving animals were approved by the university Animal Ethics Committee. Animal licenses, (16-97) in DH/HA&P/8/2/5 Pt.5 and (18-129) in DH/SHS/8/2/5 Pt.4, were approved by Department of Health of the Government of Hong Kong Special Administration Region.

Version history

  1. Received: July 19, 2019
  2. Accepted: February 10, 2020
  3. Accepted Manuscript published: February 11, 2020 (version 1)
  4. Version of Record published: March 16, 2020 (version 2)

Copyright

© 2020, Xie et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 4,745
    views
  • 787
    downloads
  • 58
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Kai Xie
  2. Naixiang Wang
  3. Xudong Lin
  4. Zixun Wang
  5. Xi Zhao
  6. Peilin Fang
  7. Haibing Yue
  8. Junhwi Kim
  9. Jing Luo
  10. Shaoyang Cui
  11. Feng Yan
  12. Peng Shi
(2020)
Organic electrochemical transistor arrays for real-time mapping of evoked neurotransmitter release in vivo
eLife 9:e50345.
https://doi.org/10.7554/eLife.50345

Share this article

https://doi.org/10.7554/eLife.50345

Further reading

    1. Biochemistry and Chemical Biology
    2. Plant Biology
    Henning Mühlenbeck, Yuko Tsutsui ... Cyril Zipfel
    Research Article

    Transmembrane signaling by plant receptor kinases (RKs) has long been thought to involve reciprocal trans-phosphorylation of their intracellular kinase domains. The fact that many of these are pseudokinase domains, however, suggests that additional mechanisms must govern RK signaling activation. Non-catalytic signaling mechanisms of protein kinase domains have been described in metazoans, but information is scarce for plants. Recently, a non-catalytic function was reported for the leucine-rich repeat (LRR)-RK subfamily XIIa member EFR (elongation factor Tu receptor) and phosphorylation-dependent conformational changes were proposed to regulate signaling of RKs with non-RD kinase domains. Here, using EFR as a model, we describe a non-catalytic activation mechanism for LRR-RKs with non-RD kinase domains. EFR is an active kinase, but a kinase-dead variant retains the ability to enhance catalytic activity of its co-receptor kinase BAK1/SERK3 (brassinosteroid insensitive 1-associated kinase 1/somatic embryogenesis receptor kinase 3). Applying hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis and designing homology-based intragenic suppressor mutations, we provide evidence that the EFR kinase domain must adopt its active conformation in order to activate BAK1 allosterically, likely by supporting αC-helix positioning in BAK1. Our results suggest a conformational toggle model for signaling, in which BAK1 first phosphorylates EFR in the activation loop to stabilize its active conformation, allowing EFR in turn to allosterically activate BAK1.

    1. Biochemistry and Chemical Biology
    2. Neuroscience
    Katarzyna Marta Zoltowska, Utpal Das ... Lucía Chávez-Gutiérrez
    Research Article

    Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17–42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.