123 TSPO expression in healthy and diseased brain knockout mice), the astrocytic proliferation and the behavioural signs, both associated with EAE, were milder, compared to wild-type animals143. Importantly, treatment with the TSPO ligand etifoxine decreases the severity and increases the symptomatic recovery in a EAE mouse model of MS142. These findings suggest that the microglial and astrocytic TSPO differentially contribute to animal models of MS. Alzheimer’s disease Alzheimer’s disease (AD) is characterized by the accumulation of amyloid deposits mainly formed by the beta amyloid peptide (Aβ) and by the presence of neurofibrillary tangles formed from abnormal forms of the Tau protein. Animal genetic models of the disease are produced by the induction of Aβ overexpression (by adding transgenes encoding human forms of APP or PS1) or overexpression of abnormal forms of Tau (by adding transgenes coding for human Tau forms)147. In all AD models, an overexpression of TSPO is observed2,5,146,148-151,158-160. However, there is no consensus on the cellular origin of TSPO161. Indeed, in the APP23 transgenic (Tg) mice model, astrocytes represent the cellular source of TSPO expression in the vicinity of extracellular amyloid deposits146. In contrast to this model, the PS19 Tg mice show microglia TSPO expression146. The presence of a significant spatial correlation between[3H](R)-PK11195 binding and IBA1 staining that is not present in the case of GFAP staining, suggests that the origin of TSPO is predominantly microglial in the APPSWE/PSEN1∆E9 mice model 2. However, double-immunofluorescence revealed that the cellular origin of TSPO may mainly be microglial although TSPO+GFAP+ cells were also present148. The predominance of a microglial origin to the TSPO binding is also observed in the 3xTgAD model (APPSWE/PS1M146V/TauP301L) with the use of IBA1 and GFAP co-staining with TSPO150. In a model combining three APP mutations and two PS1 mutations (5XFAD), colocalization of TSPO with GFAP or S100β for astrocytes is absent while TSPO+IBA1+ cells are observed. Interestingly, Liu et al. (2005) also reported that subtypes of microglial cells are differentially contributing to the expression of TSPO. Indeed, TSPO strongly colocalizes with the CD68 microglial pro-inflammatory marker. In addition, TSPO is also present in microglia positive for the CD206 anti-inflammatory marker when these cells are in the vicinity of the amyloid deposits148. Thus, the complexity of glial cell types and the differential expression of TSPO by the various subclasses of glial cells add another level of complexity that needs to be further studied. Schizophrenia In contrast to the aforementioned pathologies, the density of TSPO is decreased in schizophrenia (see details in the next chapter). Using the maternal immune activation (MIA) animal model of schizophrenia, a decrease in the TSPO levels was reported162. The authors observed a decrease in colocalization of TSPO with IBA1, GFAP, and Glut1 (a marker of the brain vasculature)162, suggesting the involvement of multiple different cell types. General considerations Overall, it is important to discuss several critical issues. First, the assessment of TSPO in other cell types than microglia has not been examined systematically, e.g. in astrocytes and even less in endothelial cells. Secondly, many studies use IBA1 as a marker of microglia, but it represents a ubiquitous labelling of this cell type and not of any specific activated forms or phenotypes. Without a more in-depth analysis of the TSPO+IBA1+ cells, it cannot be completely affirmed that it is indeed active microglia and even if it is, the pathophysiological significance of a particular phenotype of activated microglia or indeed other cells of the
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