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

T. Notter, Jennifer Marie Coughlin, T. Gschwind, U. Weber-Stadlbauer, Yuchuan Wang, M. Kassiou, A. C. Vernon, D. Benke, Martin Gilbert Pomper, Akira Sawa, U. Meyer

Research output: Contribution to journalArticle

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.Molecular Psychiatry advance online publication, 17 January 2017; doi:10.1038/mp.2016.248.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Jan 17 2017

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Schizophrenia
Positron-Emission Tomography
Proteins
Microglia
Gliosis
Cytokines
Inflammation
Protein Binding
Kainic Acid
Mental Disorders
Astrocytes
Psychiatry
Publications
Endothelial Cells
Biomarkers
Ligands
Injections
Infection

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Cite this

Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia. / Notter, T.; Coughlin, Jennifer Marie; Gschwind, T.; Weber-Stadlbauer, U.; Wang, Yuchuan; Kassiou, M.; Vernon, A. C.; Benke, D.; Pomper, Martin Gilbert; Sawa, Akira; Meyer, U.

In: Molecular Psychiatry, 17.01.2017.

Research output: Contribution to journalArticle

Notter, T. ; Coughlin, Jennifer Marie ; Gschwind, T. ; Weber-Stadlbauer, U. ; Wang, Yuchuan ; Kassiou, M. ; Vernon, A. C. ; Benke, D. ; Pomper, Martin Gilbert ; Sawa, Akira ; Meyer, U. / Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia. In: Molecular Psychiatry. 2017.
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AU - Wang, Yuchuan

AU - Kassiou, M.

AU - Vernon, A. C.

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