Nr3C1-Bhlhb2 Axis Dysregulation Is Involved in the Development of Attention Deficit Hyperactivity
Li Hui Wu1,2, Wei Cheng3,4, Mei Yu3,4
1Department of Children's Health Care, The Second Affiliated Hospital & Yu Ying Children's Hospital, Wenzhou Medical University, Wenzhou, China. jaemny@163.com.
Insights
Glucocorticoid receptor (Nr3c1) and Bhlhb2 axis dysregulation contributes to attention deficit hyperactivity disorder (ADHD). Silencing Bhlhb2 in ADHD model rats improved hyperactivity, suggesting a therapeutic target.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Genetics
Background:
- Attention deficit hyperactivity disorder (ADHD) is a developmental disorder impacting education and development.
- The prefrontal cortex (PFC) is a key brain region affected in ADHD.
- MicroRNAs (miRNAs) are implicated as potential regulators in neurodevelopmental disorders.
Purpose of the Study:
- To investigate key regulators in the PFC involved in ADHD.
- To elucidate the molecular mechanisms underlying ADHD pathogenesis.
- To identify potential therapeutic targets for ADHD.
Main Methods:
- Analysis of miRNA and gene expression in ADHD model rats (SHRs) vs. controls (WKY).
- Promoter activity assays to identify transcriptional regulation.
- Luciferase reporter assays to confirm miRNA-mRNA interactions.
- In vitro cell differentiation assays and in vivo gene silencing experiments.
Main Results:
- Downregulation of miR-138, 138*, 34c*, 296, and 494 in the PFC of SHRs.
- Elevated Nr3c1 expression inhibited the transcription of these miRNAs.
- Bhlhb2 was identified as a common target of these miRNAs and was upregulated in SHRs.
- Bhlhb2 overexpression suppressed cell differentiation; Bhlhb2 knockdown enhanced neurite growth.
- In vivo knockdown of Bhlhb2 significantly improved hyperactivity in SHRs.
Conclusions:
- The Nr3c1-Bhlhb2 axis is dysregulated in ADHD.
- Nr3c1 inhibits the expression of specific miRNAs that target Bhlhb2.
- Bhlhb2 plays a critical role in neuronal development and hyperactivity.
- Targeting the Nr3c1-Bhlhb2 pathway may offer a novel therapeutic strategy for ADHD.
Abstract:
Attention deficit hyperactivity disorder (ADHD) is a child developmental and behavioral disorder which seriously hinders their education and development. To investigate the key regulators in the prefrontal cortex (PFC), the major affected areas of ADHD, microRNA (miR)-138,138*, 34c*, 296, and 494, were noted for their significant downregulation in ADHD model rats spontaneously hypertensive rats (SHRs) compared to Wistar Kyoto (WKY) rat control. Based on promoter sequence analysis and activity assay, glucocorticoid receptor (Nr3c1) was identified for the inhibition of the promoter activity of miR-138-1, 34c*, 296, and 494 genes and their transcription. In the PFC of ADHD model rats SHR, Nr3c1 expression was abnormally elevated and reversely correlated with the levels of miR-138-1, 34c, 296, and 494 expression. Luciferase report assays indicated that all miR-138, 138*, 34c*, 296, and 494 targeted the 3' untranslated region of transcription factor Bhlhb2 (Bhlhe40) messenger RNA (mRNA) in common and ectopic expression of miR-138,138*, 34c*, 296, and 494 further suppressed the expression of Bhlhb2 gene. Consistently, Bhlhb2 expression was significantly higher in PFC of ADHD model SHR than control. Overexpressed Bhlhb2 in vitro significantly suppressed PC12 cell differentiation, and silence of Bhlhb2 enhanced the growth of neurite axon and dendrite. To observe the roles of Bhlhb2 further in vivo, Bhlhb2 was silenced in the PFC of nine SHR rats. Interestingly, knockdown of Bhlhb2 significantly improved the hyperactivity behaviors in SHRs compared to control. These findings show that Nr3c1-Bhlhb2 axis dysregulation was involved in the development of attention deficit and hyperactivity.
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