Etude du rôle du récepteur aux hydrocarbures aromatiques ou AhR dans le développement et l’homéostasie du système nerveux de la souris C57BL/6J

摘要

The AhR is a basic helix-loop-helix Per/ARNT/Sim family (bHLH-PAS) transcription factor which is activated by many diverse compounds including polyphenols and aromatic hydrocarbons such as 2,3,7,8 TétraChloroDibenzo-p-Dioxin (TCDD). Initially, the AhR was described as a ubiquitous xenobiotic-activated transcription factor which promotes the elimination of xenobiotics by regulating the expression of genes involved in xenobiotic metabolism. However, mouse AhR knockout models have demonstrated that the AhR also regulates other normal physiological functions. In particular, functioning of the nervous system of mammals, previously unexplored in this respect, might depend upon the activity of the AhR. We, thus, performed behavioral and gene expression studies in AhR-/- mice to discover these functions. We, first, found that AhR-/- mice exhibit an oculomotor deficit which is characterized by spontaneous horizontal pendular eye movements that are probably due to a deficit in the visuo-motor circuitry. Second, we found that the cerebellar gene expression profiles of AhR-/- as compared to AhR+/+ mice resembled those of AhR+/+ mice treated with TCDD (the ligand with the highest affinity for the AhR). This suggests that TCDD disrupts some normal physiological functions of the AhR in the nervous system. Third, AhR-/- mice and AhR+/+ treated with TCDD both develop liver fibrosis. This further suggests a role for the AhR in normal liver function. In conclusion, this study reveals new physiological functions for the AhR in the mouse nervous system and describes a new model of pendular nystagmus. Moreover, the results also provide novel research perspectives in the field of neurotoxicology.