NURR1 deficiency is associated to ADHD-like phenotypes in mice

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.

Working Memory Deficits in Schizophrenia Are Associated With the Rs34884856 Variant and Expression Levels of the NR4A2 Gene in a Sample Mexican Population: A Case Control Study

“…Our results are consistent with previous studies that show that the NR4A2 gene dosage is signi cantly related to cognitive function in animal models of schizophrenia [18,19]. The association of NR4A2 de ciency and reduction in performance on cognitive tasks has been reported for Alzheimer´s disease and attention-de cit hyperactivity disorder animal models [17,20], as well as with reports of its important role in diverse memory tasks in preclinical studies [16,[21][22][23][24]. NR4A2 is also involved in neurodevelopmental disorders and cognitive de cits as reported in clinical trials [14,15].…”

“…Notably, in relation to this gene, Nurr1 heterozygous (+/-) mice show cognitive impairment and pharmacological responses consistent with a model for schizophrenia [18,19]. This correlation between NR4A2 de ciency and cognitive skills has been found in other animal models for Alzheimer´s disease and attention-de cit hyperactivity disorder [17,20] as well as its particular role in memory tasks as reported in preclinical studies [16,[21][22][23][24].…”

“…Alteration in the NR4A2 gene has been proposed as animal model of schizophrenia [18,19]. Furthermore, different animal models and clinical studies support the importance of the NR4A2 gene in cognitive processes [17,20,21]. In particular, several studies support the important role of NR4A2 in memory [16,18,[21][22][23][24].…”

α-Synuclein Negatively Regulates Nurr1 Expression Through NF-κB-Related Mechanism

“…Mutation and overexpression of α-SYN can cause PD, but it is unclear why mutation and overexpression of α-SYN mostly affect DA neurons in the substantia nigra (Decressac et al, 2012). Previous studies have shown that Nurr1 is a critical modulator for the development and function of midbrain DA neurons (Jankovic et al, 2005;Kadkhodaei et al, 2009Kadkhodaei et al, , 2013Montarolo et al, 2019), and regulates genes of the DA signaling pathway, including TH, AADC, and DAT (Saucedo-Cardenas et al, 1998;Kadkhodaei et al, 2009;Raina et al, 2020). In this study, we have demonstrated that α-SYN can reduce several DA-associated gene expressions via its down-regulation on Nurr1 (Figures 3A,B), indicating that the suppression of Nurr1 expression by α-SYN overexpression is an important molecular basis for DA neuron dysfunction.…”

Loss-of-function of the NOMO1 Gene Causes Neuropsychiatric Disorder-related Phenotypes

“…Several studies have illustrated a potential functional mechanism in midbrain and hindbrain development and behavioral abnormalities, showing abnormal gene expression [38][39][40]. These aberrantly expressed genes are likely to be involved in different signaling pathways.…”