Neocortical excitation/inhibition balance in information processing and social dysfunction

Ofer Yizhar; Lief E. Fenno; Matthias Prigge; Franziska Schneider; Thomas J. Davidson; Daniel J. Ogshea; Vikaas S. Sohal; Inbal Goshen; Joel Finkelstein; Jeanne T. Paz; Katja Stehfest; Roman Fudim; Charu Ramakrishnan; John R. Huguenard; Peter Hegemann; Karl Deisseroth

doi:10.1038/nature10360

Neocortical excitation/inhibition balance in information processing and social dysfunction

Ofer Yizhar^*, Lief E. Fenno, Matthias Prigge, Franziska Schneider, Thomas J. Davidson, Daniel J. Ogshea, Vikaas S. Sohal, Inbal Goshen, Joel Finkelstein, Jeanne T. Paz, Katja Stehfest, Roman Fudim, Charu Ramakrishnan, John R. Huguenard, Peter Hegemann, Karl Deisseroth

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1791 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	171-178
Number of pages	8
Journal	Nature
Volume	477
Issue number	7363
DOIs	https://doi.org/10.1038/nature10360
State	Published - 8 Sep 2011
Externally published	Yes

Bibliographical note

Funding Information:
Acknowledgements We thank the K.D., P.H. and J.R.H. laboratories for discussions on the manuscript. We are grateful to S. Pak, Z. Chen and C. Perry for technical assistance. O.Y. is supported by the Human Frontier Science Program. L.E.F. is supported by the Stanford MSTP program. P.H. is supported by the DFG (HE3824/9-1 and 17-1, Cluster of Excellence: Unifying Concepts in Catalysis), and K.D. by NIMH, NIDA, NINDS, the DARPA REPAIR program, CIRM and the Yu, Woo, Snyder and Keck Foundations.

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Yizhar, O., Fenno, L. E., Prigge, M., Schneider, F., Davidson, T. J., Ogshea, 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. (2011). Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature, 477(7363), 171-178. https://doi.org/10.1038/nature10360

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title = "Neocortical excitation/inhibition balance in information processing and social dysfunction",

abstract = "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.",

author = "Ofer Yizhar and Fenno, {Lief E.} and Matthias Prigge and Franziska Schneider and Davidson, {Thomas J.} and Ogshea, {Daniel J.} and Sohal, {Vikaas S.} and Inbal Goshen and Joel Finkelstein and Paz, {Jeanne T.} and Katja Stehfest and Roman Fudim and Charu Ramakrishnan and Huguenard, {John R.} and Peter Hegemann and Karl Deisseroth",

note = "Funding Information: Acknowledgements We thank the K.D., P.H. and J.R.H. laboratories for discussions on the manuscript. We are grateful to S. Pak, Z. Chen and C. Perry for technical assistance. O.Y. is supported by the Human Frontier Science Program. L.E.F. is supported by the Stanford MSTP program. P.H. is supported by the DFG (HE3824/9-1 and 17-1, Cluster of Excellence: Unifying Concepts in Catalysis), and K.D. by NIMH, NIDA, NINDS, the DARPA REPAIR program, CIRM and the Yu, Woo, Snyder and Keck Foundations.",

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Yizhar, O, Fenno, LE, Prigge, M, Schneider, F, Davidson, TJ, Ogshea, DJ, Sohal, VS, Goshen, I, Finkelstein, J, Paz, JT, Stehfest, K, Fudim, R, Ramakrishnan, C, Huguenard, JR, Hegemann, P & Deisseroth, K 2011, 'Neocortical excitation/inhibition balance in information processing and social dysfunction', Nature, vol. 477, no. 7363, pp. 171-178. https://doi.org/10.1038/nature10360

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AU - Yizhar, Ofer

AU - Fenno, Lief E.

AU - Prigge, Matthias

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AU - Davidson, Thomas J.

AU - Ogshea, Daniel J.

AU - Sohal, Vikaas S.

AU - Goshen, Inbal

AU - Finkelstein, Joel

AU - Paz, Jeanne T.

AU - Stehfest, Katja

AU - Fudim, Roman

AU - Ramakrishnan, Charu

AU - Huguenard, John R.

AU - Hegemann, Peter

AU - Deisseroth, Karl

N1 - Funding Information: Acknowledgements We thank the K.D., P.H. and J.R.H. laboratories for discussions on the manuscript. We are grateful to S. Pak, Z. Chen and C. Perry for technical assistance. O.Y. is supported by the Human Frontier Science Program. L.E.F. is supported by the Stanford MSTP program. P.H. is supported by the DFG (HE3824/9-1 and 17-1, Cluster of Excellence: Unifying Concepts in Catalysis), and K.D. by NIMH, NIDA, NINDS, the DARPA REPAIR program, CIRM and the Yu, Woo, Snyder and Keck Foundations.

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N2 - 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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Neocortical excitation/inhibition balance in information processing and social dysfunction

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