Translocator protein (TSPO) and stress cascades in mouse models of psychosis with inflammatory disturbances

Fukudome, Daisuke; Hayes, Lindsay N.; Faust, Travis E.; Foss, Catherine A.; Kondo, Mari A.; Lee, Brian J.; Saito, Atsushi; Kano, Shin-ichi; Coughlin, Jennifer M.; Kamiya, Atsushi; Pomper, Martin G.; Sawa, Akira; Niwa, Minae

doi:10.1016/j.schres.2018.01.015

Cited by 9 publications

(9 citation statements)

References 65 publications

(96 reference statements)

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“…In line with previous results [41,56], we found a region-dependent increase of [18F]-GE180 uptake in cuprizone-treated mice (Figure 2A). A visual interpretation of the TSPO μPET scans indicated increased tracer uptake, particularly in the corpus callosum, caudoputamen, thalamus and cortex regions (Figure 2B).…”

Section: Resultssupporting

confidence: 93%

“…In this study, we were able to demonstrate that cuprizone-induced demyelination is paralleled by an increase in TSPO radioligand (18F)-GE180 uptake. Comparably, increased uptake of different TSPO ligands, namely, [ 3 H]-(R)-PK11195 [58,68], (123I)-CLINDE [41], and (125I)iodo-DPA-713 [56], has been shown in the cuprizone model. It was suggested that, in the cuprizone model, the observed increase in [3H]-R-PK11195 binding is a result of an increase in the apparent number of binding sites rather than a change in receptor binding affinity [58].…”

Section: Discussionmentioning

confidence: 99%

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Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models

Nack

Brendel

Nedelcu

et al. 2019

Cells

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Positron emission tomography (PET) ligands targeting the translocator protein (TSPO) represent promising tools to visualize neuroinflammation in multiple sclerosis (MS). Although it is known that TSPO is expressed in the outer mitochondria membrane, its cellular localization in the central nervous system under physiological and pathological conditions is not entirely clear. The purpose of this study was to assess the feasibility of utilizing PET imaging with the TSPO tracer, [18F]-GE180, to detect histopathological changes during experimental demyelination, and to determine which cell types express TSPO. C57BL/6 mice were fed with cuprizone for up to 5 weeks to induce demyelination. Groups of mice were investigated by [18F]-GE180 PET imaging at week 5. Recruitment of peripheral immune cells was triggered by combining cuprizone intoxication with MOG35–55 immunization (i.e., Cup/EAE). Immunofluorescence double-labelling and transgene mice were used to determine which cell types express TSPO. [18F]-GE180-PET reliably detected the cuprizone-induced pathology in various white and grey matter regions, including the corpus callosum, cortex, hippocampus, thalamus and caudoputamen. Cuprizone-induced demyelination was paralleled by an increase in TSPO expression, glia activation and axonal injury. Most of the microglia and around one-third of the astrocytes expressed TSPO. TSPO expression induction was more severe in the white matter corpus callosum compared to the grey matter cortex. Although mitochondria accumulate at sites of focal axonal injury, these mitochondria do not express TSPO. In Cup/EAE mice, both microglia and recruited monocytes contribute to the TSPO expressing cell populations. These findings support the notion that TSPO is a valuable marker for the in vivo visualization and quantification of neuropathological changes in the MS brain. The pathological substrate of an increase in TSPO-ligand binding might be diverse including microglia activation, peripheral monocyte recruitment, or astrocytosis, but not axonal injury.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models

Nack

Brendel

Nedelcu

et al. 2019

Cells

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“…the HC and thalamus in vivo . Our results add more detailed regional information to previous studies that have shown increased TSPO binding using ex vivo autoradiography in the CPZ model during demyelination and remyelination phases 49, 52-54.…”

Section: Discussionsupporting

confidence: 73%

Molecular Imaging of Immune Cell Dynamics During De- and Remyelination in the Cuprizone Model of Multiple Sclerosis by [¹⁸F]DPA-714 PET and MRI

Zinnhardt¹,

Belloy²,

Fricke³

et al. 2019

Theranostics

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Background : Activation and dysregulation of innate, adaptive and resident immune cells in response to damage determine the pathophysiology of demyelinating disorders. Among the plethora of involved cells, microglia/macrophages and astrocytes play an important role in the pathogenesis of demyelinating disorders. The in-depth investigation of the spatio-temporal profile of these cell types in vivo may inform about the exact disease state and localization as well as may allow to monitor therapeutic modulation of the components of the neuroinflammatory response during the course of multiple sclerosis (MS). In this study, we aimed to non-invasively decipher the degree and temporal profile of neuroinflammation (TSPO - [ 18 F]DPA-714 PET) in relation to selected magnetic resonance imaging (MRI) parameters (T 2 maps) in the cuprizone (CPZ)-induced model of demyelination. Methods: C57Bl6 ( n=30 ) mice were fed with a standard chow mixed with 0.2% (w/w) CPZ for 4 ( n=10 ; demyelination) and 6 weeks ( n=10 ; spontaneous remyelination). The degree of neuroinflammation at de- and remyelination was assessed by [ 18 F]DPA-714 PET, multi-echo T 2 MRI, autoradiography and immunohistochemistry. Results : CPZ-induced brain alterations were confirmed by increase of T 2 relaxation times in both white and grey matter after 3 and 5 weeks of CPZ. Peak [ 18 F]DPA-714 was found in the corpus callosum (CC, white matter), the hippocampus (HC, grey matter) and thalamus (grey matter) after 4 weeks of CPZ treatment and declined after 6 weeks of CPZ. Ex vivo autoradiography and dedicated immunofluorescence showed demyelination/remyelination with corresponding increased/decreased TSPO levels in the CC and hippocampus, confirming the spatial distribution of [ 18 F]DPA-714 in vivo . The expression of TSPO microglia and astrocytes is time-dependent in this model. Microglia predominantly express TSPO at demyelination, while the majority of astrocytes express TSPO during remyelination. The combination of PET- and MRI-based imaging biomarkers demonstrated the regional and temporal development of the CPZ model-associated neuroinflammatory response in grey and white matter regions. Conclusions : The combination of [ 18 F]DPA-714 PET and T 2 mapping may allow to further elucidate the regional and temporal profile of inflammatory signals depending on the myelination status, although the underlying inflammatory microenvironment changes. A combination of the described imaging biomarkers may facilitate the development of patient-tailored strategies for immunomodulatory and neuro-restorative therapies in MS.

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“…However while TSPO-based PET imaging signals have often been considered to support neuroinflammatory theories of disease [ 9 – 11 ], it appears difficult, if not impossible, to define the precise pathophysiological meanings and cellular sources of altered TSPO binding in such studies. In some pathological conditions, increased TSPO expression may primarily reflect ongoing inflammatory processes [ 58 – 60 ], whereas in others it may signify anomalies in cellular metabolism and energy production [ 17 ], oxidative stress [ 61 ], and/or neuronal activity (present findings). The ambiguity of conceiving TSPO simply as a biomarker of neuroinflammation or microglial activation warrants caution, and supports the urgent development of novel approaches for assessing changes in inflammatory states in the brain [ 4 , 62 , 63 ].…”

Section: Discussionmentioning

confidence: 60%

Neuronal activity increases translocator protein (TSPO) levels

et al. 2020

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The mitochondrial protein, translocator protein (TSPO), is a widely used biomarker of neuroinflammation, but its nonselective cellular expression pattern implies roles beyond inflammatory processes. In the present study, we investigated whether neuronal activity modifies TSPO levels in the adult central nervous system. First, we used single-cell RNA sequencing to generate a cellular landscape of basal TSPO gene expression in the hippocampus of adult (12 weeks old) C57BL6/N mice, followed by confocal laser scanning microscopy to verify TSPO protein in neuronal and non-neuronal cell populations. We then quantified TSPO mRNA and protein levels after stimulating neuronal activity with distinct stimuli, including designer receptors exclusively activated by designer drugs (DREADDs), exposure to a novel environment and acute treatment with the psychostimulant drug, amphetamine. Single-cell RNA sequencing demonstrated a non-selective and multi-cellular gene expression pattern of TSPO at basal conditions in the adult mouse hippocampus. Confocal laser scanning microscopy confirmed that TSPO protein is present in neuronal and non-neuronal (astrocytes, microglia, vascular endothelial cells) cells of cortical (medial prefrontal cortex) and subcortical (hippocampus) brain regions. Stimulating neuronal activity through chemogenetic (DREADDs), physiological (novel environment exposure) or psychopharmacological (amphetamine treatment) approaches led to consistent increases in TSPO gene and protein levels in neurons, but not in microglia or astrocytes. Taken together, our findings show that neuronal activity has the potential to modify TSPO levels in the adult central nervous system. These findings challenge the general assumption that altered TSPO expression or binding unequivocally mirrors ongoing neuroinflammation and emphasize the need to consider non-inflammatory interpretations in some physiological or pathological contexts.

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Translocator protein (TSPO) and stress cascades in mouse models of psychosis with inflammatory disturbances

Cited by 9 publications

References 65 publications

Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models

Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models

Molecular Imaging of Immune Cell Dynamics During De- and Remyelination in the Cuprizone Model of Multiple Sclerosis by [¹⁸F]DPA-714 PET and MRI

Neuronal activity increases translocator protein (TSPO) levels

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Translocator protein (TSPO) and stress cascades in mouse models of psychosis with inflammatory disturbances

Cited by 9 publications

References 65 publications

Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models

Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models

Molecular Imaging of Immune Cell Dynamics During De- and Remyelination in the Cuprizone Model of Multiple Sclerosis by [18F]DPA-714 PET and MRI

Neuronal activity increases translocator protein (TSPO) levels

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Molecular Imaging of Immune Cell Dynamics During De- and Remyelination in the Cuprizone Model of Multiple Sclerosis by [¹⁸F]DPA-714 PET and MRI