Neocortical excitation/inhibition balance in information processing and social dysfunction

By Ofer Yizhar, Lief Ericsson Fenno, Matthias Prigge, F. Schneider, T. J. Davidson, D. O’Shea, V. Sohal, I. Goshen, Joel Finkelstein, J. Paz and 6 more. Nature, 2011

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Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30–80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Social Psychology

View Paper: https://www.semanticscholar.org/paper/3cfbf399d76398af774ac0a973b3aeac262dcbc6

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Citations in the corpus

Optogenetic tools for analyzing the neural circuits of behavior (2011, background): “…channelrho-dopsins that are faster or slower to turn off after illumination [e.g. several channelrhodopsin mutants, including ChETA, SFO and the ChR2(D156A) mutant [20 – 22]] and color-shifted channelrhodopsins (e.g. VChR1, MChR1 and C1V1 [23 – 26]), with new variants arising at a rapid pace [27].”
Guided Variational Autoencoder for Disentanglement Learning (2020, background): “This is analogous to the excitation-inhibition mechanism [43, 53] or the explaining-away [52] phenomena.”
Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits (2014, neutral): “…a secondary mechanism in response to an imbalance between excitatory and inhibitory neurotransmission, identified in both Mecp2 mutant mice and Tsc1-deficient mice and implicated in ASD-associated stereotypies and social behavioral deficits (Chao et al., 2010; Fu et al., 2012; Yizhar et al., 2011).”
Electrical and synaptic integration of glioma into neural circuits (2019, positive): “High gamma frequency (70–110 Hz) power, a measure that correlates with neuronal firing rate and local field potential 29 and that is elevated by cortical hyperexcitability 30 , was sampled over a 3-minute period while the subjects were in a resting state.”
EEG and MEG: relevance to neuroscience. (2013, background): “…disorders, such as schizophrenia and autism, has been put forward by Uhlhaas and Singer (2012), supported by experimental evidence of abnormal cortical g oscillations in these neuropsychiatric disorders and also in some animal models with behavioral disturbances (Yizhar et al., 2011).”
Closed-loop and activity-guided optogenetic control. (2015, positive): “…and Recce, 1993), that changes in GABAergic and cholinergic tone can alter the amplitude and frequency of the theta oscillation (Lee et al., 1994; Yoder and Pang, 2005), that the same cell might be involved in rapid replay events during sharp-wave ripples when the mouse is not running (Skaggs…”
Inferring Synaptic Excitation/Inhibition Balance from Field Potentials (2016, neutral): “(B) AMPA and GABAA conductance profiles follow a difference-of-exponentials with different rise and decay time constants.”
Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity (2014, positive): “Interestingly, it has been proposed that an elevation of this ratio is a major cause of autism spectrum disorder [133, 134]; a pathology in that elevated levels of TNF-α in cerebrospinal fluid has been described [135].”
Structural plasticity of GABAergic axons is regulated by network activity and GABAA receptor activation (2013, background): “ORIGINAL RESEARCH ARTICLE published: 26 June 2013 doi: 10.3389/fncir.2013.00113 Structural plasticity of GABAergic axons is regulated by network activity and GABA receptor activationA”