TSPO in diverse CNS pathologies and psychiatric disease: A critical review and a way forward

Abstract

The use of Translocator Protein 18 kDa (TSPO) as a clinical neuroimaging biomarker of brain injury and neuroinflammation has increased exponentially in the last decade. There has been a furious pace in the development of new radiotracers for TSPO positron emission tomography (PET) imaging and its use has now been extensively described in many neurological and mental disorders. This fast pace of research and the ever-increasing number of new laboratories entering the field often times lack an appreciation of the historical perspective of the field and introduce dogmatic, but unproven facts, related to the underlying neurobiology of the TSPO response to brain injury and neuroinflammation. Paradoxically, while in neurodegenerative disorders and in all types of CNS pathologies brain TSPO levels increase, a new observation in psychiatric disorders such as schizophrenia is decreased brain levels of TSPO measured by PET. The neurobiological bases for this new finding is currently not known, but rigorous experimental design using multiple experimental approaches and careful interpretation of results is critically important to provide the methodological and/or biological underpinnings to this new observation. This review provides a perspective of the early history of validating TSPO as a biomarker of brain injury and neuroinflammation and a critical analysis of controversial topics in the literature related to the cellular sources of the TSPO response. The latter is important in order to provide the correct interpretation of PET studies in neurodegenerative and psychiatric disorders. Furthermore, this review proposes some yet to be explored explanations to new findings in psychiatric disorders and new approaches to quantitatively assess the glial sources of the TSPO response in order to move the field forward.

Keywords: Astrocytes; Biomarker; Microglia; Neurodegenerative disease; Neuroinflammation; Positron Emission Tomography (PET); Schizophrenia; Translocator protein 18 kDa (TSPO) - peripheral benzodiazepine receptor (PBR).

Figure 1:

Temporal colocalization of TSPO with glial markers in wildtype (WT) and Sandhoff disease (SD) mice in the thalamus. A) Representative triple labeled immunofluorescent confocal images in the thalamus of WT and SD mice at four different ages. Triple labeled immunofluorescent confocal imaging confirmed that TSPO colocalized with the microglial marker Mac-1 as indicated by the purple and magenta colors and astrocyte marker GFAP as indicated by the yellow color. B) In the thalamus, the percent colocalization of TSPO with Mac1 follows a similar pattern in both the WT and SD mice, with a more pronounced effect in the SD mice. The percent colocalization between TSPO and Mac-1 increases with age in both WT and SD mice and peaks at the 2 months of age. C) The percent colocalization between TSPO and GFAP also differs significantly between WT and SD mice, due to the low signal of both in the WT mice. In the SD mice, we observed a high degree of colocalization beginning at 1.5 months and remaining at 3 months of age. Each value represents the mean ± SEM. n = 3 – 4 animals and experiments. “Reprinted from Neurobiology of Disease, 85, MK Loth, J Choi, JL McGlothan, MV Pletnikov, MG Pomper, TR Guilarte, TSPO in a murine model of Sandhoff disease: presymptomatic marker of neurodegeneration and disease pathophysiology, 174-186, 2016, with permission from Elsevier.”