Monitoring ATP dynamics in electrically active white matter tracts

  1. Andrea Trevisiol
  2. Aiman S Saab
  3. Ulrike Winkler
  4. Grit Marx
  5. Hiromi Imamura
  6. Wiebke Möbius
  7. Kathrin Kusch
  8. Klaus-Armin Nave  Is a corresponding author
  9. Johannes Hirrlinger  Is a corresponding author
  1. Max-Planck-Institute for Experimental Medicine, Germany
  2. University of Leipzig, Germany
  3. Kyoto University, Japan

Abstract

In several neurodegenerative diseases and myelin disorders, the degeneration profiles of myelinated axons are compatible with underlying energy deficits. However, it is presently impossible to measure selectively axonal ATP levels in the electrically active nervous system. We combined transgenic expression of an ATP-sensor in neurons of mice with confocal FRET imaging and electrophysiological recordings of acutely isolated optic nerves. This allowed us to monitor dynamic changes and activity-dependent axonal ATP homeostasis at the cellular level and in real time. We find that changes in ATP levels correlate well with compound action potentials. However, this correlation is disrupted when metabolism of lactate is inhibited, suggesting that axonal glycolysis products are not sufficient to maintain mitochondrial energy metabolism of electrically active axons. The combined monitoring of cellular ATP and electrical activity is a novel tool to study neuronal and glial energy metabolism in normal physiology and in models of neurodegenerative disorders.

Article and author information

Author details

  1. Andrea Trevisiol

    Department of Neurogenetics, Max-Planck-Institute for Experimental Medicine, Göttingen, Germany
    Competing interests
    No competing interests declared.
  2. Aiman S Saab

    Department of Neurogenetics, Max-Planck-Institute for Experimental Medicine, Göttingen, Germany
    Competing interests
    No competing interests declared.
  3. Ulrike Winkler

    Carl-Ludwig-Institute for Physiology, University of Leipzig, Leipzig, Germany
    Competing interests
    No competing interests declared.
  4. Grit Marx

    Carl-Ludwig-Institute for Physiology, University of Leipzig, Leipzig, Germany
    Competing interests
    No competing interests declared.
  5. Hiromi Imamura

    Graduate School of Biostudies, Kyoto University, Sakyo-ku, Japan
    Competing interests
    No competing interests declared.
  6. Wiebke Möbius

    Department of Neurogenetics, Max-Planck-Institute for Experimental Medicine, Göttingen, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2902-7165
  7. Kathrin Kusch

    Department of Neurogenetics, Max-Planck-Institute for Experimental Medicine, Göttingen, Germany
    Competing interests
    No competing interests declared.
  8. Klaus-Armin Nave

    Department of Neurogenetics, Max-Planck-Institute for Experimental Medicine, Göttingen, Germany
    For correspondence
    nave@em.mpg.de
    Competing interests
    Klaus-Armin Nave, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8724-9666
  9. Johannes Hirrlinger

    Department of Neurogenetics, Max-Planck-Institute for Experimental Medicine, Göttingen, Germany
    For correspondence
    johannes.hirrlinger@medizin.uni-leipzig.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6327-0089

Funding

Deutsche Forschungsgemeinschaft

  • Johannes Hirrlinger

H2020 European Research Council

  • Klaus-Armin Nave

European Molecular Biology Organization

  • Aiman S Saab

LAVES Niedersachsen).LTLT/involved_commentsGTGTLTLTinvolved_indGTGT1LTLT/involved_indGTGTLTLT/animal_subjectsGTGTLTLThuman_subjectsGTGTLTLTinvolved_indGTGT0LTLT/involved_indGTGTLTLT/human_subjectsGTGTLTLT/xmlGTGT"

Ethics

Animal experimentation: Animals were treated in accordance with the German Protection of Animals Act (TSchG {section sign}4 Abs. 3), with the guidelines for the welfare of experimental animals issued by the European Communities Council Directive 2010/63/EU as well as the regulation of the institutional "Tierschutzkommission" and the local authorities (T04/13, T20/16; Landesdirektion Leipzig, LAVES Niedersachsen).

Copyright

© 2017, Trevisiol 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

  • 4,571
    views
  • 986
    downloads
  • 111
    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. Andrea Trevisiol
  2. Aiman S Saab
  3. Ulrike Winkler
  4. Grit Marx
  5. Hiromi Imamura
  6. Wiebke Möbius
  7. Kathrin Kusch
  8. Klaus-Armin Nave
  9. Johannes Hirrlinger
(2017)
Monitoring ATP dynamics in electrically active white matter tracts
eLife 6:e24241.
https://doi.org/10.7554/eLife.24241

Share this article

https://doi.org/10.7554/eLife.24241

Further reading

    1. Neuroscience
    Simonas Griesius, Amy Richardson, Dimitri Michael Kullmann
    Research Article

    Non-linear summation of synaptic inputs to the dendrites of pyramidal neurons has been proposed to increase the computation capacity of neurons through coincidence detection, signal amplification, and additional logic operations such as XOR. Supralinear dendritic integration has been documented extensively in principal neurons, mediated by several voltage-dependent conductances. It has also been reported in parvalbumin-positive hippocampal basket cells, in dendrites innervated by feedback excitatory synapses. Whether other interneurons, which support feed-forward or feedback inhibition of principal neuron dendrites, also exhibit local non-linear integration of synaptic excitation is not known. Here, we use patch-clamp electrophysiology, and two-photon calcium imaging and glutamate uncaging, to show that supralinear dendritic integration of near-synchronous spatially clustered glutamate-receptor mediated depolarization occurs in NDNF-positive neurogliaform cells and oriens-lacunosum moleculare interneurons in the mouse hippocampus. Supralinear summation was detected via recordings of somatic depolarizations elicited by uncaging of glutamate on dendritic fragments, and, in neurogliaform cells, by concurrent imaging of dendritic calcium transients. Supralinearity was abolished by blocking NMDA receptors (NMDARs) but resisted blockade of voltage-gated sodium channels. Blocking L-type calcium channels abolished supralinear calcium signalling but only had a minor effect on voltage supralinearity. Dendritic boosting of spatially clustered synaptic signals argues for previously unappreciated computational complexity in dendrite-projecting inhibitory cells of the hippocampus.

    1. Neuroscience
    Christine Ahrends, Mark W Woolrich, Diego Vidaurre
    Tools and Resources

    Predicting an individual’s cognitive traits or clinical condition using brain signals is a central goal in modern neuroscience. This is commonly done using either structural aspects, such as structural connectivity or cortical thickness, or aggregated measures of brain activity that average over time. But these approaches are missing a central aspect of brain function: the unique ways in which an individual’s brain activity unfolds over time. One reason why these dynamic patterns are not usually considered is that they have to be described by complex, high-dimensional models; and it is unclear how best to use these models for prediction. We here propose an approach that describes dynamic functional connectivity and amplitude patterns using a Hidden Markov model (HMM) and combines it with the Fisher kernel, which can be used to predict individual traits. The Fisher kernel is constructed from the HMM in a mathematically principled manner, thereby preserving the structure of the underlying model. We show here, in fMRI data, that the HMM-Fisher kernel approach is accurate and reliable. We compare the Fisher kernel to other prediction methods, both time-varying and time-averaged functional connectivity-based models. Our approach leverages information about an individual’s time-varying amplitude and functional connectivity for prediction and has broad applications in cognitive neuroscience and personalised medicine.