1. Medicine
  2. Neuroscience
Download icon

Autism: Balancing excitation and inhibition in the autistic brain

  1. Charlotte M Pretzsch
  2. Dorothea L Floris  Is a corresponding author
  1. Department of Forensic and Neurodevelopmental Sciences, Kings' College London, United Kingdom
  2. Donders Centre for Cognitive Neuroimaging, Netherlands
Insight
  • Cited 0
  • Views 1,055
  • Annotations
Cite this article as: eLife 2020;9:e60584 doi: 10.7554/eLife.60584

Abstract

A metric called the Hurst exponent could be a useful biomarker for studies exploring brain differences between men and women with autism spectrum disorder.

Main text

Balance and stability are important for the human body. This is clearly true for some physical tasks, such as walking or running without falling over, but it is also true inside the brain. Neurons receive both excitatory and inhibitory inputs, and maintaining a balance between the two – that is, maintaining what is known as the excitation-inhibition or E:I balance – is crucial for the brain to work properly (Yizhar et al., 2011).

Disruptions to the E:I balance, such as increased levels of excitatory inputs, have been linked to autism and a number of other neurological conditions, and can affect brain function and social behavior (Rubenstein and Merzenich, 2003). It has also been shown that the E:I balance can depend on sex, especially in regions of the brain that support social behavior, such as the ventromedial prefrontal cortex (Lai et al., 2019). However, research into the relationships between autism, sex and social behavior have been hampered by a lack of non-invasive tools. Now, in eLife, Michael Lombardo (Istituto Italiano di Tecnologia and University of Cambridge) and colleagues – including Stavros Trakoshis and Pablo Martínez-Cañada as joint first authors – report how it may be possible to measure the E:I balance without causing damage to the brain (Trakoshis et al., 2020).

The researchers – who are based in Italy, Cyprus, South Korea, the United Kingdom, Switzerland, and Canada – first created a computational model of the brain and used data from this model to calculate a metric called the Hurst exponent. This metric is a measure of the long-term memory of a time series of data. The model was then tweaked to simulate the effect of a ligand called CNO (which is short for clozapine-N-oxide) on two receptors hM3Dq and hM4Di, which are synthetic proteins designed to bind synthetic drugs. When CNO binds to hM3Dq it increases excitation, and when it binds to hM4Di it reduces both excitation and inhibition. Trakoshis et al. found that the change in the E:I balance caused by CNO also changed the Hurst exponent: specifically, an increase in excitation decreased the Hurst exponent (Figure 1).

Maintaining a balance of excitatory and inhibitory input in neurons.

An imbalance between excitatory and inhibitory inputs to neurons in certain regions of the brain has been linked to neuropsychiatric conditions such as autism spectrum disorder (ASD). However, it is not possible to measure such imbalances directly, so it would be useful to have a proxy marker. Based on computer simulations and experiments on genetically manipulated mice (top), Trakoshis et al. found that a metric called the Hurst exponent, which can be determined using non-invasive electrical and magnetic measurements, can provide information on imbalances between excitatory and inhibitory input. In particular, an increase in excitation (E) led to a decrease in the Hurst exponent (H). Experiments on autistic and typically developing (TD) men and women show that: i) the value of H for men with autism is much lower than the value for TD men; ii) the value of H for women with autism is higher than the value for TD women; iii) in women with autism, the value of H further correlated with social behavior.

Second, the researchers tested if they could replicate these computational results in mice that had undergone chemogenetic manipulation to express hM3Dq and hM4Di. This involved measuring electrical activity in the prefrontal cortex of the mice before, during and after the administration of CNO, and then computing the Hurst exponent. They found that the in vivo results in mice confirmed the predictions of their computational model. Specifically, a drug-induced increase in excitation led to a decrease in the Hurst exponent.

Third, Trakoshis et al. wanted to find out why E:I processes may differ between males and females. They found that genes associated with autism that also affect the E:I balance (especially excitation) overlapped with genes that are sensitive to male-specific hormones. A comparison of these results with a gene expression map called the Allan Human Brain Atlas (Hawrylycz et al., 2012) further revealed that these genes are expressed in many regions of the brain, including the ventromedial prefrontal cortex.

To investigate how the E:I balance may differ between autistic men and women, and how those differences may relate to social behavior, Trakoshis et al. collected neural time series data and computed the Hurst exponent in individuals with and without autism (who were similar in age and IQ). In the ventromedial prefrontal cortex, the Hurst exponent of individuals with autism was lower than that of typically developing individuals, with the difference between the two being larger in males than in females. Moreover, in women with autism, the Hurst exponent was linked with social behavior: a higher (i.e., more typical) value was accompanied by a better ability to 'socially camouflage' – that is, the ability to compensate for social-communicative difficulties.

Taken together, these results suggest that the Hurst exponent may be a useful biomarker to examine the E:I balance and its relationship with sex and social behavior across the autism spectrum. More research is needed to investigate if shifting the E:I balance in the ventromedial prefrontal cortex could alter social behavior in people with autism. In the future, this approach could be extended into other conditions linked to E:I balance and sex-differences, such as attention deficit hyperactivity disorder.

References

  1. 1
  2. 2
  3. 3
  4. 4
  5. 5

Article and author information

Author details

  1. Charlotte M Pretzsch

    Charlotte M Pretzsch is in the Department of Forensic and Neurodevelopmental Sciences, Kings' College London, United Kingdom

    Contributed equally with
    Dorothea L Floris
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2761-6628
  2. Dorothea L Floris

    Dorothea L Floris is in the Donders Centre for Cognitive Neuroimaging, Nijmegen, Netherlands

    Contributed equally with
    Charlotte M Pretzsch
    For correspondence
    D.floris@donders.ru.nl
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5838-6821

Publication history

  1. Version of Record published: August 4, 2020 (version 1)

Copyright

© 2020, Pretzsch and Floris

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,055
    Page views
  • 131
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Immunology and Inflammation
    2. Medicine
    Shubhanshi Trivedi et al.
    Research Article Updated

    Sepsis is a systemic inflammatory response to infection and a leading cause of death. Mucosal-associated invariant T (MAIT) cells are innate-like T cells enriched in mucosal tissues that recognize bacterial ligands. We investigated MAIT cells during clinical and experimental sepsis, and their contribution to host responses. In experimental sepsis, MAIT-deficient mice had significantly increased mortality and bacterial load, and reduced tissue-specific cytokine responses. MAIT cells of WT mice expressed lower levels of IFN-γ and IL-17a during sepsis compared to sham surgery, changes not seen in non-MAIT T cells. MAIT cells of patients at sepsis presentation were significantly reduced in frequency compared to healthy donors, and were more activated, with decreased IFN-γ production, compared to both healthy donors and paired 90-day samples. Our data suggest that MAIT cells are highly activated and become dysfunctional during clinical sepsis, and contribute to tissue-specific cytokine responses that are protective against mortality during experimental sepsis.

    1. Cell Biology
    2. Medicine
    LouJin Song et al.
    Research Article

    The lymphatic vasculature is involved in the pathogenesis of acute cardiac injuries, but little is known about its role in chronic cardiac dysfunction. Here, we demonstrate that angiotensin II infusion induced cardiac inflammation and fibrosis at 1 week and caused cardiac dysfunction and impaired lymphatic transport at 6 weeks in mice, while co-administration of VEGFCc156s improved these parameters. To identify novel mechanisms underlying this protection, RNA sequencing analysis in distinct cell populations revealed that VEGFCc156s specifically modulated angiotensin II-induced inflammatory responses in cardiac and peripheral lymphatic endothelial cells. Furthermore, telemetry studies showed that while angiotensin II increased blood pressure acutely in all animals, VEGFCc156s-treated animals displayed a delayed systemic reduction in blood pressure independent of alterations in angiotensin II-mediated aortic stiffness. Overall, these results demonstrate that VEGFCc156s had a multifaceted therapeutic effect to prevent angiotensin II-induced cardiac dysfunction by improving cardiac lymphatic function, alleviating fibrosis and inflammation, and ameliorating hypertension.