A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex

Abstract

Healthy neuronal networks rely on homeostatic plasticity to maintain stable firing rates despite changing synaptic drive. These mechanisms, however, can themselves be destabilizing if activated inappropriately or excessively. For example, prolonged activity deprivation can lead to rebound hyperactivity and seizures. While many forms of homeostasis have been described, whether and how the magnitude of homeostatic plasticity is constrained remains unknown. Here we uncover negative regulation of cortical network homeostasis by the PARbZIP family of transcription factors. In cortical slice cultures made from knockout mice lacking all three of these factors, the network response to prolonged activity withdrawal measured with calcium imaging is much stronger, while baseline activity is unchanged. Whole cell recordings reveal an exaggerated increase in the frequency of miniature excitatory synaptic currents reflecting enhanced upregulation of recurrent excitatory synaptic transmission. Genetic analyses reveal that two of the factors, Hlf and Tef, are critical for constraining plasticity and for preventing life-threatening seizures. These data indicate that transcriptional activation is not only required for many forms of homeostatic plasticity but is also involved in restraint of the response to activity deprivation.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files, calcium imaging analysis code is available http://github.com/VH-Lab/vhlab-TwoPhoton-matlab. RNAseq data have been deposited to the BioSample database.

Article and author information

Author details

  1. Vera Valakh

    Department of Biology, Brandeis University, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7149-1562
  2. Derek Wise

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  3. Xiaoyue Aelita Zhu

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  4. Mingqi Sha

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  5. Jaidyn Fok

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  6. Stephen D Van Hooser

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1112-5832
  7. Robin Schectman

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  8. Isabel Cepeda

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  9. Ryan Kirk

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  10. Sean M O'Toole

    Department of Biology, Brandeis University, Cambridge, United States
    Competing interests
    No competing interests declared.
  11. Sacha B Nelson

    Department of Biology, Brandeis University, Waltham, United States
    For correspondence
    nelson@brandeis.edu
    Competing interests
    Sacha B Nelson, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0108-8599

Funding

National Institute of Neurological Disorders and Stroke (R01NS109916)

  • Sacha B Nelson

Simons Foundation Autism Research Initiative (648651)

  • Sacha B Nelson

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 procedures were approved by the Institutional Animal Care and Use Committee at Brandeis University (Protocol #20002), and conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Copyright

© 2023, Valakh 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. Vera Valakh
  2. Derek Wise
  3. Xiaoyue Aelita Zhu
  4. Mingqi Sha
  5. Jaidyn Fok
  6. Stephen D Van Hooser
  7. Robin Schectman
  8. Isabel Cepeda
  9. Ryan Kirk
  10. Sean M O'Toole
  11. Sacha B Nelson
(2023)
A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex
eLife 12:e74899.
https://doi.org/10.7554/eLife.74899

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https://doi.org/10.7554/eLife.74899