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

  1. Ohad Stoler
  2. Alexandra Stavsky
  3. Yana Khrapunsky
  4. Israel Melamed
  5. Grace E Stutzmann
  6. Daniel Gitler
  7. Israel Sekler  Is a corresponding author
  8. Ilya Fleidervish  Is a corresponding author
  1. Ben Gurion University of the Negev, Israel
  2. Rosalind Franklin University of Medicine and Science, United States

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

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

    Depatrment of Physiology and Cell Biology, 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

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

    Depatrment of Physiology and Cell Biology, Ben Gurion University of the Negev, Beer Sheva, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Grace E Stutzmann

    Rosalind Franklin University of Medicine and Science, North Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel Gitler

    Depatrment of Physiology and Cell Biology, 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:" 0000-0001-9544-3610
  7. Israel Sekler

    Depatrment of Physiology and Cell Biology, 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

    Depatrment of Physiology and Cell Biology, 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

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

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).

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.

Metrics

  • 1,744
    views
  • 367
    downloads
  • 16
    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. Ohad Stoler
  2. Alexandra Stavsky
  3. Yana Khrapunsky
  4. Israel Melamed
  5. Grace E Stutzmann
  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
eLife 11:e74606.
https://doi.org/10.7554/eLife.74606

Share this article

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

Further reading

    1. Neuroscience
    Giordano de Guglielmo, Lieselot Carrette ... Olivier George
    Research Article

    Addiction is commonly characterized by escalation of drug intake, compulsive drug seeking, and continued use despite harmful consequences. However, the factors contributing to the transition from moderate drug use to these problematic patterns remain unclear, particularly regarding the role of sex. Many preclinical studies have been limited by small sample sizes, low genetic diversity, and restricted drug access, making it challenging to model significant levels of intoxication or dependence and translate findings to humans. To address these limitations, we characterized addiction-like behaviors in a large sample of >500 outbred heterogeneous stock (HS) rats using an extended cocaine self-administration paradigm (6 hr/daily). We analyzed individual differences in escalation of intake, progressive ratio (PR) responding, continued use despite adverse consequences (contingent foot shocks), and irritability-like behavior during withdrawal. Principal component analysis showed that escalation of intake, progressive ratio responding, and continued use despite adverse consequences loaded onto a single factor that was distinct from irritability-like behaviors. Categorizing rats into resilient, mild, moderate, and severe addiction-like phenotypes showed that females exhibited higher addiction-like behaviors, with a lower proportion of resilient individuals compared to males. These findings suggest that, in genetically diverse rats with extended drug access, escalation of intake, continued use despite adverse consequences, and PR responding are highly correlated measures of a shared underlying construct. Furthermore, our results highlight sex differences in resilience to addiction-like behaviors.

    1. Neuroscience
    Tingting Li, Wenwen Shi ... Yong Q Zhang
    Research Article

    Traumatic brain injury (TBI) caused by external mechanical forces is a major health burden worldwide, but the underlying mechanism in glia remains largely unclear. We report herein that Drosophila adults exhibit a defective blood–brain barrier, elevated innate immune responses, and astrocyte swelling upon consecutive strikes with a high-impact trauma device. RNA sequencing (RNA-seq) analysis of these astrocytes revealed upregulated expression of genes encoding PDGF and VEGF receptor-related (Pvr, a receptor tyrosine kinase), adaptor protein complex 1 (AP-1, a transcription factor complex of the c-Jun N-terminal kinase pathway) composed of Jun-related antigen (Jra) and kayak (kay), and matrix metalloproteinase 1 (Mmp1) following TBI. Interestingly, Pvr is both required and sufficient for AP-1 and Mmp1 upregulation, while knockdown of AP-1 expression in the background of Pvr overexpression in astrocytes rescued Mmp1 upregulation upon TBI, indicating that Pvr acts as the upstream receptor for the downstream AP-1–Mmp1 transduction. Moreover, dynamin-associated endocytosis was found to be an important regulatory step in downregulating Pvr signaling. Our results identify a new Pvr–AP-1–Mmp1 signaling pathway in astrocytes in response to TBI, providing potential targets for developing new therapeutic strategies for TBI.