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Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia

Abstract

Positron emission tomography (PET) imaging with radiotracers that target translocator protein 18 kDa (TSPO) has become a popular approach to assess putative neuroinflammatory processes and associated microglia activation in psychotic illnesses. It remains unclear, however, whether TSPO imaging can accurately capture low-grade inflammatory processes such as those present in schizophrenia and related disorders. Therefore, we evaluated the validity of TSPO as a disease-relevant marker of inflammation using a translational approach, which combined neurodevelopmental and neurodegenerative mouse models with PET imaging in patients with recent-onset schizophrenia and matched controls. Using an infection-mediated neurodevelopmental mouse model, we show that schizophrenia-relevant behavioral abnormalities and increased inflammatory cytokine expression are associated with reduced prefrontal TSPO levels. On the other hand, TSPO was markedly upregulated in a mouse model of acute neurodegeneration and reactive gliosis, which was induced by intrahippocampal injection of kainic acid. In both models, the changes in TSPO levels were not restricted to microglia but emerged in various cell types, including microglia, astrocytes and vascular endothelial cells. Human PET imaging using the second-generation TSPO radiotracer [11C]DPA-713 revealed a strong trend towards reduced TSPO binding in the middle frontal gyrus of patients with recent-onset schizophrenia, who were previously shown to display increased levels of inflammatory cytokines in peripheral and central tissues. Together, our findings challenge the common assumption that central low-grade inflammation in schizophrenia is mirrored by increased TSPO expression or ligand binding. Our study further underscores the need to interpret altered TSPO binding in schizophrenia with caution, especially when measures of TSPO are not complemented with other markers of inflammation. Unless more selective microglial markers are available for PET imaging, quantification of cytokines and other inflammatory biomarkers, along with their molecular signaling pathways, may be more accurate in attempts to characterize inflammatory profiles in schizophrenia and other mental disorders that lack robust reactive gliosis.

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Acknowledgements

We thank Professor Jean-Marc Fritschy (Institute of Pharmacology and Toxicology, University of Zurich, Switzerland) for his technical assistance in the immunohistochemical procedures. We are also thankful to Dr Sandra Giovanoli for her assistance in behavioral experimentation and stereological analyses. This work was supported by the Swiss National Science Foundation (grant nos 310030_146217 and 310030_169544) and the Foundation for Research in Science and the Humanities at the University of Zurich awarded to UM. Additional financial support for this study was provided by NARSAD (awarded to JC and AS), the Alexander Wilson Schweizer Fellowship (awarded to JC), by a Silvio O. Conte Center grant (MH094268, awarded to AS) and by the Medical Research Council (New Investigator Grant, MR/N025377/1, awarded to ACV).

Author contributions

Study concept and design: TN, JMC, AS and UM. Generation of animal models: TN, UW and TG. Acquisition of animal data: TN, UW and DB. Analysis and interpretation of animal data: TN, UW, ACV, DB and UM. Acquisition of human data: JMC, YW, MGP and AS. Analysis and interpretation of human data: JMC, TN, YW, MGP, MK, AS and UM. Drafting of the manuscript: TN and UM. Critical revision of the manuscript for important intellectual content: TN, JMC, TG, UW, YW, KM, ACV, DB, MGP, AS and UM.

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Correspondence to A Sawa or U Meyer.

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Competing interests

ACV has previously received grant support from F. Hoffmann-La Roche Ltd. The remaining authors declare no conflict of interest. The present work is purely academic.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Notter, T., Coughlin, J., Gschwind, T. et al. Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia. Mol Psychiatry 23, 323–334 (2018). https://doi.org/10.1038/mp.2016.248

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