Targeting light-gated chloride channels to neuronal somatodendritic domain reduces their excitatory effect in the axon

  1. Jessica E Messier
  2. Hongmei Chen
  3. Zhao-Lin Cai
  4. Mingshan Xue  Is a corresponding author
  1. Baylor College of Medicine, United States

Abstract

Light-gated chloride channels are emerging as promising optogenetic tools for inhibition of neural activity. However, their effects depend on the transmembrane chloride electrochemical gradient and may be complex due to the heterogeneity of this gradient in different developmental stages, neuronal types, and subcellular compartments. Here we characterized a light-gated chloride channel, GtACR2, in mouse cortical neurons. We found that GtACR2 activation inhibited the soma, but unexpectedly depolarized the presynaptic terminals resulting in neurotransmitter release. Other light-gated chloride channels had similar effects. Reducing the chloride concentrations in the axon and presynaptic terminals diminished the GtACR2-induced neurotransmitter release, indicating an excitatory effect of chloride channels in these compartments. A novel hybrid somatodendritic targeting motif reduced the GtACR2-induced neurotransmitter release while enhancing the somatic photocurrents. Our results highlight the necessity of precisely determining the effects of light-gated chloride channels under specific experimental conditions and provide a much-improved light-gated chloride channel for optogenetic inhibition.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Jessica E Messier

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5865-7043
  2. Hongmei Chen

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Zhao-Lin Cai

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4034-2884
  4. Mingshan Xue

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    For correspondence
    Mingshan.Xue@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1463-8884

Funding

Whitehall Foundation (2015-05-54)

  • Mingshan Xue

Robert and Janice McNair Foundation (M.D./Ph.D. Student Scholarship)

  • Jessica E Messier

National Institutes of Health (R01NS100893)

  • Mingshan Xue

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All procedures to maintain and use mice were approved in the Animal Research Protocol AN-6544 by the Institutional Animal Care and Use Committee at Baylor College of Medicine.

Copyright

© 2018, Messier 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

  • 6,053
    views
  • 808
    downloads
  • 69
    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. Jessica E Messier
  2. Hongmei Chen
  3. Zhao-Lin Cai
  4. Mingshan Xue
(2018)
Targeting light-gated chloride channels to neuronal somatodendritic domain reduces their excitatory effect in the axon
eLife 7:e38506.
https://doi.org/10.7554/eLife.38506

Share this article

https://doi.org/10.7554/eLife.38506

Further reading

    1. Neuroscience
    Cristina Gil Avila, Elisabeth S May ... Markus Ploner
    Research Article

    Chronic pain is a prevalent and debilitating condition whose neural mechanisms are incompletely understood. An imbalance of cerebral excitation and inhibition (E/I), particularly in the medial prefrontal cortex (mPFC), is believed to represent a crucial mechanism in the development and maintenance of chronic pain. Thus, identifying a non-invasive, scalable marker of E/I could provide valuable insights into the neural mechanisms of chronic pain and aid in developing clinically useful biomarkers. Recently, the aperiodic component of the electroencephalography (EEG) power spectrum has been proposed to represent a non-invasive proxy for E/I. We, therefore, assessed the aperiodic component in the mPFC of resting-state EEG recordings in 149 people with chronic pain and 115 healthy participants. We found robust evidence against differences in the aperiodic component in the mPFC between people with chronic pain and healthy participants, and no correlation between the aperiodic component and pain intensity. These findings were consistent across different subtypes of chronic pain and were similarly found in a whole-brain analysis. Their robustness was supported by preregistration and multiverse analyses across many different methodological choices. Together, our results suggest that the EEG aperiodic component does not differentiate between people with chronic pain and healthy individuals. These findings and the rigorous methodological approach can guide future studies investigating non-invasive, scalable markers of cerebral dysfunction in people with chronic pain and beyond.

    1. Neuroscience
    Ankur Sinha, Padraig Gleeson ... Robin Angus Silver
    Tools and Resources

    Data-driven models of neurons and circuits are important for understanding how the properties of membrane conductances, synapses, dendrites, and the anatomical connectivity between neurons generate the complex dynamical behaviors of brain circuits in health and disease. However, the inherent complexity of these biological processes makes the construction and reuse of biologically detailed models challenging. A wide range of tools have been developed to aid their construction and simulation, but differences in design and internal representation act as technical barriers to those who wish to use data-driven models in their research workflows. NeuroML, a model description language for computational neuroscience, was developed to address this fragmentation in modeling tools. Since its inception, NeuroML has evolved into a mature community standard that encompasses a wide range of model types and approaches in computational neuroscience. It has enabled the development of a large ecosystem of interoperable open-source software tools for the creation, visualization, validation, and simulation of data-driven models. Here, we describe how the NeuroML ecosystem can be incorporated into research workflows to simplify the construction, testing, and analysis of standardized models of neural systems, and supports the FAIR (Findability, Accessibility, Interoperability, and Reusability) principles, thus promoting open, transparent and reproducible science.