Region Specific Effects of Aging and the Nurr1-Null Heterozygous Genotype on Dopamine Neurotransmission

Abstract

The transcription factor Nurr1 is essential for dopamine neuron differentiation and is important in maintaining dopamine synthesis and neurotransmission in the adult. Reduced Nurr1 function, due to the Nurr1-null heterozygous genotype (+/−), impacts dopamine neuron function in a region specific manner resulting in a decrease in dopamine synthesis in the dorsal and ventral striatum and a decrease in tissue dopamine levels in the ventral striatum. Additionally, maintenance of tissue dopamine levels in the dorsal striatum and survival of nigrostriatal dopamine neurons with aging (>15 months) or after various toxicant treatments are impaired. To further investigate the effects of aging and the Nurr1-null heterozygous genotype, we measured regional tissue dopamine levels, dopamine neuron numbers, body weight, open field activity and rota-rod performance in young (3–5 months) and aged (15–17 months) wild-type +/+ and +/− mice. Behavioral tests revealed no significant differences in rota-rod performance or basal open field activity as a result of aging or genotype. The +/− mice did show a significant increase in open field activity after 3 min of restraint stress. No differences in tissue dopamine levels were found in the dorsal striatum. However, there were significant reductions in tissue dopamine levels in the ventral striatum, which was separated into the nucleus accumbens core and shell, in the aged +/− mice. These data indicate that the mesoaccumbens system is more susceptible to the combination of aging and the +/− genotype than the nigrostriatal system. Additionally, the effects of aging and the +/− genotype may be dependent on genetic background or housing conditions. As Nurr1 mutations have been implicated in a number of diseases associated with dopamine neurotransmission, further data is needed to understand why and how Nurr1 can have differential functions across different dopamine neuron populations in aging.

NURR1 deficiency is associated to ADHD-like phenotypes in mice

“…On this matter, contrasting results can be found in the literature. According to our data, Jiang and Kummari found no alterations in the number of TH-expressing mDA in the SN of adult NURR1-KO mice 20,42 . On the contrary, Vuillermot and colleagues reported a reduction of these mDA in NURR1-KO mice of the same age 23 .…”

NURR1‐deficient mice have age‐ and sex‐specific behavioral phenotypes

“…Unlike the young, only two studies reporting conflicting results investigated the phenotype of old NURR1‐KO mice (Jiang et al, 2005; Kummari et al, 2017). Jiang and colleagues observed significant alteration in both motor and locomotor activities in old NURR1‐KO mice measured by means of rotarod and open field (OF) test, respectively (Jiang et al, 2005).…”

“…Jiang and colleagues observed significant alteration in both motor and locomotor activities in old NURR1-KO mice measured by means of rotarod and open field (OF) test, respectively (Jiang et al, 2005). This was not confirmed by Kummari and colleagues, who described no significant differences in rotarod performance and OF activity in old NURR1-KO mice in comparison to their wild-type (WT) littermates (Kummari et al, 2017).…”

Wnt1 silencing enhances neurotoxicity induced by paraquat and maneb in SH‑SY5Y cells

“…NURR1 is a transcription factor that regulates the development of DA precursors into mature DA neurons (31). In NURR1-deficient mice, DA dysfunction occurs during ageing (32)(33)(34). Therefore, NURR1 is considered to be a PD candidate gene (35).…”