Abstract
Tamoxifen is frequently used in murine knockout systems with CreER/LoxP. Besides possible neuroprotective effects, tamoxifen is described as having a negative impact on adult neurogenesis. The present study investigated the effect of a high-dose tamoxifen application on Theiler’s murine encephalomyelitis virus (TMEV)-induced hippocampal damage. Two weeks after TMEV infection, 42% of the untreated TMEV-infected mice were affected by marked inflammation with neuronal loss, whereas 58% exhibited minor inflammation without neuronal loss. Irrespective of the presence of neuronal loss, untreated mice lacked TMEV antigen expression within the hippocampus at 14 days post-infection (dpi). Interestingly, tamoxifen application 0, 2 and 4, or 5, 7 and 9 dpi decelerated virus elimination and markedly increased neuronal loss to 94%, associated with increased reactive astrogliosis at 14 dpi. T cell infiltration, microgliosis and expression of water channels were similar within the inflammatory lesions, regardless of tamoxifen application. Applied at 0, 2 and 4 dpi, tamoxifen had a negative impact on the number of doublecortin (DCX)-positive cells within the dentate gyrus (DG) at 14 dpi, without a long-lasting effect on neuronal loss at 147 dpi. Thus, tamoxifen application during a TMEV infection is associated with transiently increased neuronal loss in the hippocampus, increased reactive astrogliosis and decreased neurogenesis in the DG.
Highlights
A selective estrogen receptor modulator (SERM), is used as an inductive agent in the CreER/LoxP system, which is commonly applied in genetically modified mice with a C57BL/6 (B6) background [1]
It is commonly seen that hippocampal neuronal loss after Theiler’s murine encephalomyelitis virus (TMEV)-BeAn infection varies between not detectable and 20–50% loss of the pyramidal neurons in the CA1/CA2 sector in mice on a C57BL/6 background at 7 and 98 dpi [10]
Additional experiments in which mice were sacrificed at 7 dpi showed that there is no difference in the numbers of TMEV antigen-positive cells in the hippocampus of Tam0dpi mice at this earlier time point (Supplementary Figure S1)
Summary
A selective estrogen receptor modulator (SERM), is used as an inductive agent in the CreER/LoxP system, which is commonly applied in genetically modified mice with a C57BL/6 (B6) background [1]. The clinical course of an intracranial Theiler’s murine encephalomyelitis virus (TMEV) infection is highly variable and depends both on the virus strain as well as on the host mouse strain [8]. These factors largely determine whether animals show seizures and eliminate the virus from the central nervous system (CNS) [9,10]. The effect of tamoxifen treatment on virus elimination, T cell infiltration, hippocampal damage, neurogenesis and glial activation after TMEV infection of genetically modified floxed mice on a B6 background were investigated
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