Frequency-and spike-timing-dependent mitochondrial Ca2+ signaling regulates the metabolic rate and synaptic efficacy in cortical neurons

Abstract

Mitochondrial activity is crucial for the plasticity of central synapses, but how the firing pattern of pre- and postsynaptic neurons affects the mitochondria remains elusive. We recorded changes in the fluorescence of cytosolic and mitochondrial Ca2+ indicators in cell bodies, axons, and dendrites of cortical pyramidal neurons in mouse brain slices while evoking pre- and postsynaptic spikes. Postsynaptic spike firing elicited fast mitochondrial Ca2+ responses that were about threefold larger in the somas and apical dendrites than in basal dendrites and axons. The amplitude of these responses and metabolic activity were extremely sensitive to the firing frequency. Furthermore, while an EPSP alone caused no detectable Ca2+ elevation in the dendritic mitochondria, the coincidence of EPSP with a backpropagating spike produced prominent, highly localized mitochondrial Ca2+ hotspots. Our results indicate that mitochondria decode the spike firing frequency and the Hebbian temporal coincidences into the Ca2+ signals, which are further translated into the metabolic output and most probably lead to long-term changes in synaptic efficacy.

Data availability

A representative subset of the raw electrical recording and imaging data has been deposited to Dryad (https://doi.org/10.5061/dryad.sxksn0348). The dataset contains the Microcal Origin opj files of the electrical and optical recordings and quantitative analysis of the data. We are unable to make all raw electrical recording and imaging data publicly available as due to the large size of our raw dataset (>10TB). Interested researchers should contact the corresponding author to gain access to the raw data.

The following data sets were generated

Article and author information

Author details

  1. Ohad Stoler

    Ben Gurion University of the Negev, Beer Sheva, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Alexandra Stavsky

    Ben Gurion University of the Negev, Beer Sheva, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8209-3524
  3. Yana Khrapunsky

    Ben Gurion University of the Negev, Beer Sheva, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Israel Melamed

    Ben Gurion University of the Negev, Beer Sheva, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Grace E. Stutzmann, Ph.D.

    Ben Gurion University of the Negev, Beer Sheva, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel Gitler

    Ben Gurion University, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9544-3610
  7. Israel Sekler

    Ben Gurion University of the Negev, Beer Sheva, Israel
    For correspondence
    sekler@bgu.ac.il
    Competing interests
    The authors declare that no competing interests exist.
  8. Ilya Fleidervish

    Ben Gurion University of the Negev, Beer Sheva, Israel
    For correspondence
    ilya@bgu.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5501-726X

Funding

Israel Science Foundation (1384/19)

  • Ilya Fleidervish

Israel Science Foundation (1310/19)

  • Daniel Gitler

National Institutes of Health (RF1 AG065628)

  • Israel Sekler

National Institutes of Health (RF1 AG065628)

  • Grace E. Stutzmann, Ph.D.

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

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

Ethics

Animal experimentation: All experiments were approved by the Animal Care and Use Committee of Ben Gurion University of the Negev (protocol #IL-68-09-2019).

Version history

  1. Preprint posted: June 7, 2021 (view preprint)
  2. Received: October 11, 2021
  3. Accepted: February 20, 2022
  4. Accepted Manuscript published: February 22, 2022 (version 1)
  5. Accepted Manuscript updated: February 25, 2022 (version 2)
  6. Version of Record published: March 9, 2022 (version 3)

Copyright

© 2022, Stoler 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.

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  1. Ohad Stoler
  2. Alexandra Stavsky
  3. Yana Khrapunsky
  4. Israel Melamed
  5. Grace E. Stutzmann, Ph.D.
  6. Daniel Gitler
  7. Israel Sekler
  8. Ilya Fleidervish
(2022)
Frequency-and spike-timing-dependent mitochondrial Ca2+ signaling regulates the metabolic rate and synaptic efficacy in cortical neurons
eLife 11:e74606.
https://doi.org/10.7554/eLife.74606

Share this article

https://doi.org/10.7554/eLife.74606

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