Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

A new suspect in the unsolved case of neuroinflammation in schizophrenia

Molecular Psychiatry volume 26, pages 7105–7106 (2021)Cite this article

Subjects

As evidence implicating neuroinflammation in the pathophysiology of schizophrenia mounts, so too does evidence that microglia—the brain’s resident immune cells—are not participating as expected. At least, they do not seem to be activated in a way that is typical of other neuroinflammatory conditions. Here we call attention to a fresh hypothesis that, if correct, could help explain the microglia paradox. In their recent paper, Corsi-Zuelli and Deakin [1] posit unchecked astrocytic reactivity causes microglia to be “held” in a non-inflammatory, but still phagocytic, state; a theory that the authors weave into prominent neurodevelopmental hypotheses of schizophrenia pertaining to over-pruning of synapses during adolescence. Corsi-Zuelli and Deakin [1] draw upon various cellular, molecular and genetic lines of evidence to support their theory and are commended on their novel ideas as to what may be upstream of neuroinflammation in schizophrenia, and what may underlie the apparent lack of “inflammatory” microglia in patients. Still, this thought-provoking paper leaves some important questions unanswered, which will be essential avenues for future research in the field.

Corsi-Zuelli and Deakin [1] build their argument around three non-neuronal cell types and three main findings: (1) consistently unchanged or decreased markers of microgliosis in schizophrenia brain but increased expression of astrocyte markers via large-scale transcriptomics, (2) the capacity for the cytokine transforming growth factor-beta (TGF-β) to retain microglia in a non-inflammatory state, and (3) the function of regulatory T cells (Tregs) within the brain to suppress glial-mediated neuroinflammation, a process that is dependent on Treg-astrocyte interactions. This perspective is unique as T-cells rarely feature in theories of neuropathology in schizophrenia. The authors put T-cells in a pivotal position and propose that, in schizophrenia, faulty Tregs fail to normally interact with astrocytes, leading to unchecked astrocytic reactivity. These unchecked astrocytes then presumably secrete both pro-inflammatory mediators and the anti-inflammatory cytokine TGF-β, simultaneously causing neuroimmune activation and forcing microglia into a non-inflammatory, phagocytic state via overproduction of TGF-β. The authors go further to suggest that this propensity for increased microglial phagocytosis in patients may underlie the purported “over-pruning” of synapses during adolescence—the cornerstone of the neurodevelopmental hypothesis of schizophrenia.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Corsi-Zuelli F, Deakin B. Impaired regulatory T cell control of astroglial overdrive and microglial pruning in schizophrenia. Neurosci Biobehav Rev. 2021;125:637–53.

    Article  CAS  Google Scholar 

  2. Dubbelaar ML, Kracht L, Eggen BJL, Boddeke EWGM. The kaleidoscope of microglial phenotypes. Front Immunol. 2018;9:1753.

    Article  Google Scholar 

  3. Zhu Y, Webster MJ, Murphy CE, Middleton F, Shannon Weickert C (2021). Molecular evidence that macrophages contribute more to cortical neuroinflammation in people with schizophrenia than do microglia. Poster presentation T4 at SIRS virtual conference 2021.

  4. Beasley C, Hercher C, Hill S, Tai AMY (2021). Altered microglial morphology in prefrontal cortex in schizophrenia. Poster presentation T82 at SIRS virtual conference 2021.

  5. Lopez-Gonzalez I, Pinacho R, Vila E, Escanilla A, Ferrer I, Ramos B. Neuroinflammation in the dorsolateral prefrontal cortex in elderly chronic schizophrenia. Eur Neuropsychopharmacol. 2019;29:384–96.

    Article  CAS  Google Scholar 

  6. Purves-Tyson T, Robinson K, Brown AM, Boerrigter D, Cai HQ, Weissleder C, et al. Increased macrophages and C1qA, C3, C4 transcripts in the midbrain of people with schizophrenia. Front Immunol. 2019;11:2002.

    Article  Google Scholar 

  7. Kumar BV, Connors T, Farber DL. Human T cell development, localization, and function throughout life. Immunity. 2018;48:202–13.

    Article  CAS  Google Scholar 

  8. Schlaaff K, Dobrowolny H, Frodl T, Mawrin C, Gos T, Steiner J, et al. Increased densities of T and B lymphocytes indicate neuroinflammation in subgroups of schizophrenia and mood disorder patients. Brain Behav Immunol. 2020;88:497–506.

    Article  CAS  Google Scholar 

  9. Kipnis J, Gadani S, Derecki NC. Pro-cognitive properties of T cells. Nat Rev Immunol. 2012;12:663–9.

    Article  CAS  Google Scholar 

  10. Riberio M, Brigas HC, Temido-Ferreira M, Pousinha PA, Regen T, et al. Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory. Sci Immunol. 2019;4:eaay5199.

    Article  Google Scholar 

  11. de Lima A, et al. Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons. Nat Immunol. 2020;21:1421–9.

    Article  Google Scholar 

Download references

Acknowledgements

CSW is funded by the NSW Ministry of Health, Office of Health and Medical Research. CSW is a recipient of a National Health and Medical Research Council (Australia) Principal Research Fellowship (PRF) (#1117079). CSW is in collaboration with Astellas Pharma Inc., Japan.

Author information

Authors and Affiliations

  1. Neuroscience Research Australia, Sydney, Australia

    Caitlin E. Murphy & Cynthia Shannon Weickert

  2. School of Psychiatry, University of New South Wales, Sydney, Australia

    Cynthia Shannon Weickert

  3. Department of Neuroscience & Physiology, Upstate Medical University, Syracuse, NY, USA

    Cynthia Shannon Weickert

Authors
  1. Caitlin E. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cynthia Shannon Weickert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cynthia Shannon Weickert.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Murphy, C.E., Weickert, C.S. A new suspect in the unsolved case of neuroinflammation in schizophrenia. Mol Psychiatry 26, 7105–7106 (2021). https://doi.org/10.1038/s41380-021-01225-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01225-8

This article is cited by

Search

Advanced search

Quick links