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

Abstract

13A leading theory holds that neurodevelopmental brain disorders arise from imbalances in 14 excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-15 dimensional model is rich enough to capture the multiple neural circuit alterations 16 underlying brain disorders. Here we combined computational simulations with analysis of in 17 vivo 2-photon Ca 2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a 18 model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: 1) The E/I 19 imbalance model cannot account for joint alterations in the observed neural firing rates and 20 correlations; 2) Neural circuit function is vastly more sensitive to changes in some cellular 21 components over others; 3) The direction of circuit alterations in Fmr1 KO mice changes 22 across development. These findings suggest that the basic E/I imbalance model should be 23 updated to higher-dimensional models that can better capture the multidimensional 24 computational functions of neural circuits. 25. CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/086363 doi: bioRxiv preprint first posted online Nov. 7, 2016; O'Donnell et al.2

Genetic mutations in Ca2+ signaling alter dendrite morphology and social approach in juvenile mice

“…67 Juvenile Fmr1−/− mice have elevated synchrony in the firing of cortical neurons as indicated by in vivo calcium imaging, especially during the first two postnatal weeks. 68,69 Together these results highlight elevated calcium signaling as a convergent pathway of both T4826I-RYR1 gain-of-function mutation and CGG models. Given the importance of calcium signaling in dendritic morphology and connectivity, it is possible that altered calcium signaling contributes to the effect on dendritic morphology of each genetic mutation observed in this study.…”

“…Furthermore, in human fibroblasts with FMR1 CGG repeats, pharmacological destabilization of CGG repeat RNA restores calcium dynamics . Juvenile Fmr1−/− mice have elevated synchrony in the firing of cortical neurons as indicated by in vivo calcium imaging, especially during the first two postnatal weeks . Together these results highlight elevated calcium signaling as a convergent pathway of both T4826I‐ RYR1 gain‐of‐function mutation and CGG models.…”

Inhibitory neurons are a Central Controlling regulator in the effective cortical microconnectome

“…Historically, it had been known that suppression of inhibitory neurons causes less selectivity for external stimuli [Sillito, 1975]. However, it is also true that E/I balance is an oversimplified quantification when considering the inherently wide diversity and non-uniformity of huge numbers of neurons [Nelson, Valakh, 2015;O'Donnell et al, 2017]. As a fact, relative positions of individual neurons are highly non-uniform, and rare outstandingly influential neurons sometimes have exceptional ability to influence the global brain dynamics [Miles, Wang, 1983].…”

Cellular and Synaptic Phenotype Compensations Limit Circuit Disruption inFmr1-KOMouse Layer 4 Barrel Cortex but Fail to Prevent Deficits in Information Processing

“…Rodent models demonstrate that the sensory hypersensitivities associated with Fmr1 deletion are mirrored by an increase in circuit excitability (Zhang et al, 2012;He et al, 2017He et al, , 2018O'Donnell et al, 2017). However, the known cellular processes that contribute to circuit hyperexcitability in Fmr1-KO mice are numerous (Contractor, Klyachko and Portera-Cailliau, 2015) and the potential number is even greater.…”

“…Hence, a detailed dissection of the contribution of individual cellular phenotypes underlying the emergent circuit pathophysiology is required to understand the sensory processing deficits associated with FXS (O'Donnell et al, 2017).…”