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