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Neocortical excitation/inhibition balance in information processing and social dysfunction

Nature volume 477, pages 171–178 (2011)Cite this article

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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.

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Author notes

  1. Ofer Yizhar and Lief E. Fenno: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Bioengineering, W083 Clark Center, 318 Campus Drive West, Stanford University, Stanford, California, USA

    Ofer Yizhar, Lief E. Fenno, Thomas J. Davidson, Daniel J. O’Shea, Vikaas S. Sohal, Inbal Goshen, Joel Finkelstein, Charu Ramakrishnan & Karl Deisseroth

  2. Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel

    Ofer Yizhar

  3. Neuroscience Program, W083 Clark Center, 318 Campus Drive West, Stanford University, Stanford, 94305, California, USA

    Lief E. Fenno & Daniel J. O’Shea

  4. Institute of Biology, Experimental Biophysics, Humboldt-Universität, Invalidenstraße 42, D-10115 Berlin, Germany

    Matthias Prigge, Franziska Schneider, Katja Stehfest, Roman Fudim & Peter Hegemann

  5. Department of Psychiatry, University of California, San Francisco, San Francisco, 94143, California, USA

    Vikaas S. Sohal

  6. Department of Neurology and Neurological Science, W083 Clark Center, 318 Campus Drive West, Stanford University, Stanford, 94305, California, USA

    Jeanne T. Paz & John R. Huguenard

  7. Howard Hughes Medical Institute, W083 Clark Center, 318 Campus Drive West, Stanford University, Stanford, 94305, California, USA

    Karl Deisseroth

  8. Department of Psychiatry and Behavioral Sciences, W083 Clark Center, 318 Campus Drive West, Stanford University, Stanford, 94305, California, USA

    Karl Deisseroth

  9. CNC Program, W083 Clark Center, 318 Campus Drive West, Stanford University, Stanford, 94305, California, USA

    Karl Deisseroth

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  1. Ofer Yizhar
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Contributions

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.

Corresponding authors

Correspondence to Ofer Yizhar, Peter Hegemann or Karl Deisseroth.

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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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Yizhar, O., Fenno, L., Prigge, M. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011). https://doi.org/10.1038/nature10360

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  1. Carlos Ibanez

    In a mouse model of autism developed by Sudhof and colleagues (ref. 27), a mutation found in autistic patients was introduced in knock-in mice and found to cause increased inhibitory synaptic transmission and impaired social behavior. The authors of the present study dismiss this work (and results from other mouse mutant studies) as "chronic interventions" that introduce "developmental alterations". But autism is a developmental disorder with a genetic basis. Flipping the author's argument, one wonders to which extent acute manipulation of E/I balance in a normal brain mimics complex cognitive disorders with a clear genetic and developmental basis.

  2. Karl Deisseroth

    We fully concur with the point made in the comment, that the transgenic rodent is by far the best-suited experimental system for determining causal relationships among inborn genetic alterations and subsequent behavioral pathologies. Indeed, various mice with different kinds of inborn transgenic modifications have displayed social impairment in the mature animal, and in many cases diverse alterations in E/I balance in cortical and subcortical brain regions are also observed in these animals; we described and referenced much of this ''pioneering work''(Yizhar et al., Nature 2011; e.g. refs 25, 27, 28).

    The unique strength of the transgenic model lies precisely in establishing a causal relationship between genetic alteration and pathology (which certainly could involve developmental and homeostatic changes and which would therefore unquestionably be most relevant to understanding the effects of genes on behavior in human beings). The parallels with clinical care run deeper as well. It is challenging in a typical transgenic model- just as in patients where (for example) increased excitability and epilepsy comorbidity are seen in autism-- to then determine which (if any) of the physiological changes observed might be causal for the social behavioral effects seen, rather than compensatory to, or distinct from, the causal processes. It is also difficult to determine in which cells, circuits, and brain regions such a causal effect of physiology might be exerted on behavior (the latter is a particularly challenging problem for complex integrative social behaviors).

    We sought to complement the pioneering transgenic animal work with a completely different kind of experiment, which as we emphasized would fail to capture any developmental effects, but instead would test the effects of directly altered physiology in localized circuits on behavior. Our experiments targeted the prefrontal cortex, which has been implicated in executive function, working memory, affect regulation and multisensory integration, all often impaired in relevant patient populations. We observed profound and reversible deficits in mouse social interactions as a result of directly elevating E/I balance in this local circuit, as well as observing elevated baseline gamma-band power in frontal cortex (also reported in relevant human conditions).

    Moreover, our additional results revealed that E/I balance is not a simple concept, and must be considered in the context of local circuitry-dependent effects (Figure 2i; Supplementary Figure 6). For example, we reported strong region-specificity of the effect; identical E/I balance manipulations did not lead to social impairment (and even trended toward increased sociability) when carried out in primary visual cortex (Figure 2i). This result may be concordant with seminal findings from two transgenic lines that included effects on primary sensory cortices (Tabuchi et al., ref 27; Canty et al., Journal of Neuroscience 29:10695-705, 2009), suggesting that E/I balance changes observed in sensory cortices can be associated with behavioral effects distinct from and even opposing those arising from E/I changes in medial prefrontal cortex. In summary, we are in full agreement with the central point of the comment.

  3. Peter Gibson

    I liked the idea of the E/I balance. What struck me was that if there is a deficit in some people others must have been augmented. The augmented will be quicker but not necessarily brighter. Brightness, presumably, will depend on the numbers of neuronal connections but this may not be a limiting factor since, I assume, processing is will just take longer in those with fewer connections. ?He may be a slow reader but he remembers more? is probably not true but it gives the gist. Also the ?quick ones? are also too quick for their own good. They are not always great on thinking.
    There was a vogue for counting synapses in the elderly with Alzheimer?s. It was a bit pointless since ultimately these poor people (we may all end there) lose a lot more than synapses. ?Me say large numbers of synapse good ? small numbers bad.? Taking that as a theme then in our uterine days we were all geniuses. Perhaps the E/I balance depend not on the failure to produced connections but on losing too many as numbers of neurones are trimmed following birth. Halt the numbers lost and we would be as bright as buttons (but probably unable to make our minds up about anything!).
    I made a few such vague suggestions in a blog to Mottron, ?Changing perceptions ?.? Nature 479, pp. 33-35 (2 Nov 2011) and elsewhere.

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