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Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders

  1. Cian O'Donnell  Is a corresponding author
  2. J Tiago Gonçalves
  3. Carlos Portera-Cailliau
  4. Terrence J Sejnowski  Is a corresponding author
  1. University of Bristol, United Kingdom
  2. University of California, Los Angeles, United States
  3. Howard Hughes Medical Institute, Salk Institute for Biological Studies, United States
Research Article
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Cite this article as: eLife 2017;6:e26724 doi: 10.7554/eLife.26724

Abstract

A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here we combined computational simulations with analysis of in vivo 2-photon Ca2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: 1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; 2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; 3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher-dimensional models that can better capture the multidimensional computational functions of neural circuits.

Article and author information

Author details

  1. Cian O'Donnell

    Department of Computer Science, University of Bristol, Bristol, United Kingdom
    For correspondence
    cian.odonnell@bristol.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2031-9177
  2. J Tiago Gonçalves

    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Carlos Portera-Cailliau

    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Terrence J Sejnowski

    Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    terry@salk.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0622-7391

Funding

FRAXA Research Foundation (Postdoctoral fellowship)

  • Cian O'Donnell

Howard Hughes Medical Institute

  • Cian O'Donnell
  • Terrence J Sejnowski

Sloan-Swartz

  • Cian O'Donnell
  • Terrence J Sejnowski

Dana Foundation

  • J Tiago Gonçalves
  • Carlos Portera-Cailliau

John Merck Fund (20160969)

  • Carlos Portera-Cailliau

Simons Foundation (295438)

  • Carlos Portera-Cailliau

National Institute of Neurological Disorders and Stroke (RC1NS068093)

  • J Tiago Gonçalves
  • Carlos Portera-Cailliau

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD054453)

  • J Tiago Gonçalves
  • Carlos Portera-Cailliau

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 conducted according the US National Institutes of Health guidelines for animal research, under an animal protocol (ARC#2007-035) approved by the Chancellor's Animal Research Committee and the Office for the Protection of Research Subjects at the University of California, Los Angeles.

Reviewing Editor

  1. Frances K Skinner, University Health Network, Canada

Publication history

  1. Received: March 11, 2017
  2. Accepted: October 4, 2017
  3. Accepted Manuscript published: October 11, 2017 (version 1)
  4. Accepted Manuscript updated: October 13, 2017 (version 2)
  5. Version of Record published: October 31, 2017 (version 3)

Copyright

© 2017, O'Donnell 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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