Neocortical excitation/inhibition balance in information processing and social dysfunction

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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.

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Figure 1: Kinetic and absorbance properties of a stabilized SFO.
Figure 2: Elevated, but not reduced, prefrontal E/I balance leads to behavioural impairment.
Figure 3: Elevated cellular E/I balance in the mPFC drives baseline high frequency rhythmicity in freely moving, socially impaired mice.
Figure 4: Multistep engineering of a potent redshifted ChR.
Figure 5: Combinatorial optogenetics enables partial reversal of elevated E/I-balance social behaviour disruption.

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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.

Author information

O.Y., M.P., F.S. and C.R. designed and cloned all DNA constructs; O.Y. and L.E.F. contributed to all neuronal electrophysiology and behavioural experiments; T.J.D. designed the CMO implant; I.G. and J.F. contributed to behaviour and histology experiments; D.J.O. and V.S.S. contributed to slice electrophysiology and mutual information analysis; K.S. and R.F. performed spectroscopy experiments; M.P. and F.S. performed HEK cell experiments; P.H. analysed and supervised spectroscopy and HEK cell work; J.T.P. and J.R.H. conducted and analysed, and J.R.H. supervised, thalamic slice experiments. K.D. supervised all aspects of the project and O.Y., L.E.F. and K.D. wrote the manuscript.

Correspondence to Ofer Yizhar or Peter Hegemann or Karl Deisseroth.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-16 with legends, Supplementary Tables 1-2, Supplementary Methods and additional references. (PDF 3710 kb)

Supplementary Movie 1

The movie shows social interaction with a novel male juvenile in a mouse injected with CaMKII'-SSFO virus in mPFC, in the absence of light activation of SSFO. (MOV 5586 kb)

Supplementary Movie 2

The movie shows social interaction with a novel male juvenile in a mouse injected with CaMKII'-SSFO virus in mPFC, following a 1 s 473 nm light pulse to activate SSFO (MOV 4715 kb)

Supplementary Movie 3

The movie shows open field behavior in a mouse injected with CaMKII'-SSFO virus and implanted with a chronic 4-wire recording array. A 1 s 473 nm light pulse is given after 2 minutes of baseline recording, followed by a 30 s, 594 nm light pulse to deactivate SSFO (yellow light pulse starts at 4:00 minutes). (MOV 5838 kb)

Supplementary Movie 4

The movie shows social interaction with a novel male juvenile in a mouse injected with CaMKII'-SSFO virus in mPFC and implanted with a chronic 4-wire recording array, in the absence of light activation. (MOV 5094 kb)

Supplementary Movie 5

The movie shows social interaction with a novel male juvenile in the same mouse shown in Movie 4. A 1 s 473 nm light pulse was delivered 1 minute before the novel juvenile was introduced. (MOV 5473 kb)

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