Abstract
The transcription factor NURR1 regulates the dopamine (DA) signaling pathway and exerts a critical role in the development of midbrain dopaminergic neurons (mDA). NURR1 alterations have been linked to DA-associated brain disorders, such as Parkinson’s disease and schizophrenia. However, the association between NURR1 defects and the attention-deficit hyperactivity disorder (ADHD), a DA-associated brain disease characterized by hyperactivity, impulsivity and inattention, has never been demonstrated. To date, a comprehensive murine model of ADHD truly reflecting the whole complex human psychiatric disorder still does not exist. NURR1-knockout (NURR1-KO) mice have been reported to exhibit increased spontaneous locomotor activity, but their complete characterization is still lacking. In the present study a wide-ranging test battery was used to perform a comprehensive analysis of the behavioral phenotype of the male NURR1-KO mice. As a result, their hyperactive phenotype was confirmed, while their impulsive behavior was reported for the first time. On the other hand, no anxiety and alterations in motor coordination, sociability and memory were observed. Also, the number of mDA expressing tyrosine hydroxylase, a rate-limiting enzyme of catecholamines biosynthesis, and DA level in brain were not impaired in NURR1-KO mice. Finally, hyperactivity has been shown to be recovered by treatment with methylphenidate, the first line psychostimulant drug used for ADHD. Overall, our study suggests that the NURR1 deficient male mouse may be a satisfactory model to study some ADHD behavioral phenotypes and to test the clinical efficacy of potential therapeutic agents.
Highlights
Introduction The nuclear receptor related1 protein (NURR1, called NR4A2) is an orphan member of the steroid hormone receptor family
(see figure on previous page) Fig. 5 MPH rescues the altered locomotor activity of NURR1-KO mice but not their impulsive behavior. Both WT and NURR1-KO mice treated with vehicle (0.9% NaCl) or MPH (0.75 mg/kg) 1 h before were tested in the open field (OF, a, b) or cliff avoidance reaction (CAR, c, d) for 1 h. a, b The analysis disclosed that NURR1-KO mice treated with MPH show a rescue in their altered locomotor activity, in terms of distance travelled (a) (Kruskal–Wallis with Dunn’s post hoc test, df = 3, p = 0.03) and velocity (b) (Kruskal–Wallis with Dunn’s post hoc test, p < 0.0001, df = 3, p = 0.03)
The transcription factor NURR1 regulates genes of the DA signaling pathway[2,4,5] and is essential for the midbrain dopaminergic neurons (mDA) development[7,37]. This is probably due to its ability to regulate genes of the DA signaling pathway[2,4,5], and to protect mDA against inflammation-induced damage[6,7,37]
Summary
Introduction The nuclear receptor related1 protein (NURR1, called NR4A2) is an orphan member of the steroid hormone receptor family. In the present study a wide-ranging test battery was used to perform a comprehensive analysis of the behavioral phenotype of the male NURR1-KO mice. 85.7% (six out of seven) of the NURR1-KO mice fell from platforms during the 60 min observation against the 11.1% (one out of nine) of the WT mice, showing an impulsive behavior (Fig. 1f, Fisher exact test, p < 0.0001).
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