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Neocortical excitation/inhibition balance in information processing and social dysfunction
Open accessAbstract
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.
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“Conventionally used AAV backbones which include a commonly used neuronal expression cassette composed of 1.3 kb CaMKIIα promoter (which shows comparable expression efficiency with 0.4 kb CaMKIIα promoter [10] used in CWB), WPRE, and human growth hormone polyadenylation signal [23-25] has a capacity of 2.4 kb.”
From Optimization of AAV expression cassettes to improve packaging capacity and transgene expression in neurons (2014) · cites this paper as [24]
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In the citing paper
“Importantly, alterations in the balance between excitatory and inhibitory signalling in neural micro-circuitry have been implicated in social deficits as seen in ASD and SCZ (Yizhar et al. 2011).”
From Neurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia (2025) · cites this paper as Yizhar et al. 2011
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In the citing paper
“Changes in PFC network activity directly affect cognitive and social skills”
From Social Play Behavior Is Critical for the Development of Prefrontal Inhibitory Synapses and Cognitive Flexibility in Rats (2022) · cites this paper as Yizhar et al., 2011
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“Elevated levels of the repressive H3K27me3 mark, catalyzed by the histone methyltransferase EZH2, have also been observed in chronic stress models.”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Yizhar et al., 2011
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“These increases are associated with reduced expression of neuroplasticity-related genes, including CREB and enzymes involved in GABA synthesis (Yizhar et al., 2011).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Yizhar et al., 2011
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“Psychotic symptoms may be seen as attempts to garner some advantage, perhaps by convincing others of their veracity (113).”
From The Predictive Coding Account of Psychosis (2018) · cites this paper as [113]
Experimental — accuracy not yet measuredIn the citing paper
“Defective synaptic function leading to an excitation–inhibition (E/I) imbalance is commonly invoked as one possible explanation for ASD (Rubenstein and Merzenich 2003), and is supported by evidence in humans and rodents (Yizhar et al. 2011; Hashemi et al. 2017; Selimbeyoglu et al. 2017).”
From Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories (2018) · cites this paper as Yizhar et al. 2011
In the citing paper
“Yizhar et al. (2011) have shown that increased neural excitability can lead to impairments in social interaction and cognitive functions in a mouse model of autism.”
From From early markers to neuro-developmental mechanisms of autism (2014) · cites this paper as Yizhar et al., 2011
In the citing paper
“changes in mTOR-autophagy signaling and spine pruning defects may represent a secondary mechanism in response to an imbalance between excitatory and inhibitory neurotransmission”
From Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits (2014) · cites this paper as Yizhar et al., 2011
In the citing paper
“Recently, it was demonstrated that increasing neural excitation is sufficient to disrupt cognition and sociability”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Yizhar et al., 2011
In the citing paper
“E/I imbalance is a defining neurophysiological feature of neurodevelopmental disorders (Rubenstein and Merzenich, 2003) and elevated excitation is sufficient to disrupt cognition and sociability (Yizhar et al., 2011).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Yizhar et al., 2011
In the citing paper
“both constant and high frequency laser stimulation of PV cINs expressing the red-shifted opsin C1V1 in brain slices40 resulted in firing time-locked to the stimulus.”
From Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans (2020) · cites this paper as [40]
In the citing paper
“In mice, both congenital knockout and haploinsufficiency of Shank3 leads to diminished social interest in others and is associated with the disruption of cortical and subcortical circuits thought to be involved in ASD 22–26 and its ontogenesis 22,25,27,28.”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [26]
In the citing paper
“Here, we used microelectrode arrays that were implanted in the animal’s mPFC (Extended Data Fig. 1b), an area suggested to be involved in social behavior 1,7,12,26,34 and disorders such as ASD 14,21,35,36.”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [26]
In the citing paper
“we chose to use the Stabilized Step Function Opsin (SSFO), which upon activation by a single light pulse leads to prolonged (approximately 30 min) sub-threshold depolarization (Yizhar et al., 2011), sensitizing the cell to afferent inputs rather than inducing firing directly.”
From Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic Behaviors (2020) · cites this paper as Yizhar et al., 2011
In the citing paper
“This provided an estimated 1.75 mm3 of brain tissue being illuminated with light intensity above 8 microwatt×mm–2, the lowest reported functional light intensity for SSFO”
From Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic Behaviors (2020) · cites this paper as Yizhar et al., 2011
In the citing paper
“Neural circuit manipulation in combination with neural recordings provide direct evidence that elevated mPFC activity results in ASD-related phenotypes, whereas decreasing mPFC activity is sufficient to rescue abnormal behaviors in ASD models22,23,24.”
From Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits (2020) · cites this paper as [23]
In the citing paper
“Our integrative analyses have allowed us to: (a) identify disease-relevant cell types for a disorder; (b) identify unique dysfunctions in individual cohorts (due to impact on very specific subtypes); (c) deduce a potential functional basis of a disorder (such as excitatory/inhibitory balance48,49, lack of myelination50 etc.) based on the cells affected.”
From Cell type-specific transcriptional programs in mouse prefrontal cortex during adolescence and addiction (2019) · cites this paper as [49]
In the citing paper
“Disruption of the ratio of excitation and inhibition (E/I balance) can give rise to profound behavioral deficits and may play a key role in serious mental illnesses such as schizophrenia (Yizhar et al. 2011).”
From Linking microcircuit dysfunction to cognitive impairment: Effects of disinhibition associated with schizophrenia in a cortical working memory model (2014) · cites this paper as Yizhar et al. 2011
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Metadata
- Authors
- Yizhar, O., Fenno, L. E., Prigge, M., Schneider, F., Davidson, T. J., O’Shea, D. J., Sohal, V. S., Goshen, I., Finkelstein, J., Paz, J. T., Stehfest, K., Fudim, R., Ramakrishnan, C., Huguenard, J. R., Hegemann, P., & Deisseroth, K.
- Affiliations
- Stanford University (US)
- Humboldt-Universität zu Berlin (DE)
- University of California, San Francisco (US)
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Yizhar, Ofer
- Hegemann, Peter
- Deisseroth, Karl
- ORCID
- Venue
- Nature
- Published
- 2011-07-27
- Volume
- 477
- Issue
- 7363
- Pages
- 171-178
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4155501
- OpenAlex
- W2072652550
- Cited by
- 2,454
- References
- 52
- Citations by year
- 2026: 138 · 2025: 154 · 2024: 154 · 2023: 193 · 2022: 179 · 2021: 202 · 2020: 183 · 2019: 172 · 2018: 186 · 2017: 165 · 2016: 152 · 2015: 173 · 2014: 143 · 2013: 129 · 2012: 107
- FWCI
- 52.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (DP1OD000616)
- National Institute of Mental Health (R01MH075957, R01MH086373)
- National Institute of Neurological Disorders and Stroke (R01NS034774, R01NS006477)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- excitation-inhibition balance, medial prefrontal cortex, social dysfunction, autism spectrum disorder, schizophrenia, neuropsychiatric disorders, optogenetics, inhibitory interneurons, neuronal excitability, high-frequency oscillations, social behavior, learning behavior
- MeSH terms
- Animals, Autistic Disorder, Mental Disorders, Disease Models, Animal, Hippocampus, Humans, Learning, Models, Neurological, Motor Activity, Neural Inhibition, Neurons, Schizophrenia, Social Behavior, Prefrontal Cortex, Mice, Opsins, HEK293 Cells
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