Journal article
Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia.
- Notter T Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
- Coughlin JM Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
- Gschwind T Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
- Weber-Stadlbauer U Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
- Wang Y Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
- Kassiou M School of Chemistry, The University of Sydney, Sydney, NSW, Australia.
- Vernon AC MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK.
- Benke D Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
- Pomper MG Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
- Sawa A Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
- Meyer U Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
- 2017-01-18
Published in:
- Molecular psychiatry. - 2018
Adult
Animals
Astrocytes
Biomarkers
Disease Models, Animal
Female
Humans
Inflammation
Male
Mice
Mice, Inbred C57BL
Microglia
Neuroimmunomodulation
Positron-Emission Tomography
Receptors, GABA
Schizophrenia
English
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.
- Language
-
- English
- Open access status
- green
- Identifiers
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- DOI 10.1038/mp.2016.248
- PMID 28093569
- Persistent URL
- https://sonar.ch/global/documents/185236
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