NURR1 Deficiency Is Associated to Altered Microglial Phenotype in Male Mice.

Abstract

The transcription factor NUclear Receptor Related 1 (NURR1) regulates the development and maintenance of midbrain dopaminergic (mDA) neurons, which control voluntary movement, motivation, and reward. NURR1 also plays anti-inflammatory functions in microglia, protecting mDA neurons from inflammation-induced death. It remains to be determined to what extent NURR1 exerts its function in microglia. Interestingly, altered microglial phenotypes are associated to psychiatric conditions. NURR1 defects in male mice are associated with hyperactive and impulsive behaviour. Notably, such behaviour is accompanied by a normal development of mDA neurons which, at least in their number, are preserved. This study aims to explain the altered behaviour of NURR1-deficient mice by analyzing microglial compartment and inflammatory machinery that could be consistently altered to influence such observed behaviours. The present work demonstrates that NURR1 deficiency determines a reduction in the number of microglial cells specifically in the substantia nigra (SN), without altering their morphological activation state. Gene expression levels of molecules associated with active/protective microglial phenotype in the SN of NURR1^+/- mice are altered. The level of HMOX, a marker of cellular damage/apoptosis, is up-regulated, while the level of MT2, a marker of response to stress, is reduced in the SN of NURR1^+/- mice. The level of prostaglandin receptors, which are endogenous ligands for NURR1, is up-regulated in the same compartment. Overall, the NURR1-deficient mice, which exhibit impaired behaviour, have a reduced number of microglia cells and alterations of the inflammatory machinery in their SN.