Section of Oral Medicine for Children, Division of Oral Health, Growth & Development, Faculty of Dental Science, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan.
Section of Oral Medicine for Children, Division of Oral Health, Growth & Development, Faculty of Dental Science, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan.
Biochem Biophys Res Commun. 2019 Jun 11;513(4):1048-1054. doi: 10.1016/j.bbrc.2019.04.084. Epub 2019 Apr 19.
Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders and is characterized by impaired attention, hyperactivity, and impulsivity. While multiple etiologies are implicated in ADHD, its underlying mechanism(s) remain unclear. Although previous studies have suggested dysregulation of dopaminergic signals, mitochondria, and brain-derived neurotrophic factor (BDNF) in ADHD, few studies have reported these associations directly. Stem cells from human exfoliated deciduous teeth (SHED) can efficiently differentiate into dopaminergic neurons (DNs) and are thus a useful disease-specific cellular model for the study of neurodevelopmental disorders associated with DN dysfunction. This study aimed to elucidate the relationships between DNs, mitochondria, and BDNF in ADHD by analyzing DNs differentiated from SHED obtained from three boys with ADHD and comparing them to those from three typically developing boys. In the absence of exogenous BDNF in the cell culture media, DNs derived from boys with ADHD (ADHD-DNs) exhibited impaired neurite outgrowth and branching, decreased mitochondrial mass in neurites, and abnormal intracellular ATP levels. In addition, BDNF mRNA was significantly decreased in ADHD-DNs. Supplementation with BDNF, however, significantly improved neurite development and mitochondrial function in ADHD-DNs. These results suggest that ADHD-DNs may have impaired neurite development and mitochondrial function associated with insufficient production of BDNF, which may be improved by exogenous BDNF supplementation. Findings such as these, from patient-derived SHED, may contribute to the future development of treatment strategies for aberrant dopaminergic signaling, mitochondrial functioning, and BDNF levels implicated in ADHD pathogenesis.
注意缺陷多动障碍（ADHD）是最常见的神经发育障碍之一，其特征为注意力不集中、多动和冲动。尽管 ADHD 涉及多种病因，但潜在机制仍不清楚。虽然先前的研究表明，ADHD 中多巴胺能信号、线粒体和脑源性神经营养因子（BDNF）失调，但很少有研究直接报告这些关联。人脱落乳牙源性干细胞（SHED）可高效分化为多巴胺能神经元（DN），因此是研究与 DN 功能障碍相关的神经发育障碍的有用疾病特异性细胞模型。本研究旨在通过分析从三名 ADHD 男孩和三名正常发育男孩中分离的 SHED 分化而来的 DNs，阐明 ADHD 中 DNs、线粒体和 BDNF 之间的关系。在细胞培养基中缺乏外源性 BDNF 的情况下，来自 ADHD 男孩的 DNs（ADHD-DNs）表现出突起生长和分支减少、突起中线粒体质量减少和细胞内 ATP 水平异常。此外，ADHD-DNs 中的 BDNF mRNA 显著减少。然而，BDNF 的补充显著改善了 ADHD-DNs 的突起发育和线粒体功能。这些结果表明，ADHD-DNs 可能存在突起发育和线粒体功能受损，与 BDNF 产生不足有关，外源性 BDNF 补充可能改善这种情况。这些源自患者 SHED 的发现可能有助于未来制定治疗策略，以纠正 ADHD 发病机制中涉及的异常多巴胺能信号、线粒体功能和 BDNF 水平。
