Interplay of chronic mild stress, glial activation and neuroinflammation in an adult mouse model of Parkinson’s disease

To characterize the interplay among chronic mild stress (CMS), glia activation and neuroinf lammation in an adult mouse model of Parkinson’s disease (PD), 10-12 weeks old mice were randomly assigned either to control group or subjected to CMS, that was induced by exposing mice every day for 24 weeks to random stress stimuli. At the end of treatment half of control and CMS groups respectively were treated with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) that causes the selective degeneration of the substantia nigra dopaminergic neurons, the main pathological feature of human PD [1]. Glia activation was evaluated by GFAP (for astrocytes) and IBA1 (for microglia) expression; TLR4 and CD40 expression in astrocytes and microglia were evaluated as neuroinflammation activation markers. CMS effects on mice were studied by the glucocorticoid receptor (GR) nuclear translocation and expression analysis. GR shuttles from the cytoplasm to the nucleus upon binding to cortisol, where it modulates the transcription of glucocorticoid-responsive genes. The binding to its ligand leads also to GR transcriptional regulation [2]. As expected, MPTP treatment caused a strong astrocyte activation. Moreover, GFAP expression was also increased in striata of stressed animals compared to non-stressed counterparts. Microglia of MPTP-treated animals showed an activated phenotype, together with a more intense IBA1-immunoreactivity; CMS induced an increase of IBA1 immunoreactivity, too. TLR4 expression was strongly induced by MPTP treatment; in contrast, CMS alone had no significant effects on TLR4 expression in both astrocytes and microglia, as well as in stressed MPTP-treated animals. CD40/GFAP and CD40/IBA1 double labelling immunofluorescence experiments showed that CD40 expression increased in astroglia and microglia, respectively, of MPTP-treated mice. Although CMS induced glial activation, it had no effect on CD40 expression. Animals subjected to CMS alone showed both GR nuclear translocation and increased GR expression, likely as a consequence of cortisol release, whereas MPTP had no significant effects on GR translocation or expression. In mice subjects to both CMS and MPTP treatment there was no evident GR translocation and expression increase. These results show an inverse correlation between CMS-induced GR activation and pro-inflammatory markers expression; further studies are needed to investigate the effects of CMS in MPTP- treated mouse model of PD disease.