Dynamic changes of activated AHR in microglia and astrocytes in the substantia nigra-striatum system in an MPTP-induced Parkinson’s disease mouse model

Abstract

Aryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor expressed in various brain regions. However, little is known about the role of AHR during neuroinflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. Here, mice were sacrificed at day 4, day 6 and day 8 respectively after MPTP or saline treatment. Behavioral tests, Tyrosine hydroxylase (TH) expression, glial reaction, and AHR expression and activation were then assayed. As expected, mice treated with MPTP showed apparent behavioral dysfunctions and significantly reduced TH content. Immunofluorescence (IF) labeling showed an increased trend of phosphorylated AHR activation in the Substantia Nigra pars compacta (SNpc) and striatum after MPTP treatment. Western blot analysis demonstrated that MPTP treatment induced a significantly increased level of AHR at each time point tested, with the highest level observed at day 6 in the striatum. To determine exactly the AHR activation in relation to changes of glial cell reactivity, double IF labeling was performed for either IBA1 (microglia marker) and p-AHR, or GFAP (astrocyte marker) and p-AHR. The results demonstrated that MPTP treatment not only increases the number of p-AHR-positive IBA1-expressing cells in the striatum and the SNpc, but also increases that of p-AHR-positive GFAP-expressing cells in the striatum. Intriguingly, the increase of the number of cells co-expressing both p-AHR and IBA1 was highest at day 4 in response to MPTP in the striatum and at day 8 in the SNpc. The number of cells co-expressing both p-AHR and GFAP was increased at days 4, 6 and 8 in the striatum. In conclusion, our study suggests that AHR activation may facilitate PD diagnosis and serve as a target for the treatment of PD.