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

Abstract
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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.

Data availability

The following previously published data sets were used

1. Gonçalves
2. J.T
3. O'Donnell
4. C.
5. Sejnowski
6. T.J.
7. Portera-Cailliau
8. C.
(2017) Two photon Ca2+ imaging recordings of spontaneous activity from mouse somatosensory cortex in wild-type and Fmr1 knock-out mice from three developmental age groups
Available at CRCNS.org.

http://dx.doi.org/10.6080/K0X63K3X

Article and author information

Author details

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.

"This ORCID iD identifies the author of this article:" 0000-0003-2031-9177
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.
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.
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.

"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.

Copyright

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.