title: 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.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.|Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Notter
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA.|Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Coughlin
authors.affiliation: Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.|Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Gschwind
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Weber-Stadlbauer
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW, Australia.|Discipline of Medical Radiation Sciences, The University of Sydney, Sydney, NSW, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Kassiou
authors.affiliation: MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK.|King's College London, Institute of Psychiatry Psychology and Neuroscience, Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Vernon
authors.affiliation: Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.|Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Benke
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA.|Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sawa
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.|Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Meyer
mesh_terms: D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000502:physiology; D049268:Positron-Emission Tomography / Q000379:methods; D018079:Receptors, GABA / Q000032:analysis / Q000378:metabolism*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C463819:Bzrp protein, mouse; D018079:Receptors, GABA; C499229:TSPO protein, human