Aberrant extracellular dopamine clearance in the prefrontal cortex exhibits ADHD-like behavior in NCX3 heterozygous mice

Ryo Inagaki, Satomi Kita, Nozomu Niwa, Kohji Fukunaga, Takahiro Iwamoto, Shigeki Moriguchi
{"title":"Aberrant extracellular dopamine clearance in the prefrontal cortex exhibits ADHD-like behavior in NCX3 heterozygous mice","authors":"Ryo Inagaki,&nbsp;Satomi Kita,&nbsp;Nozomu Niwa,&nbsp;Kohji Fukunaga,&nbsp;Takahiro Iwamoto,&nbsp;Shigeki Moriguchi","doi":"10.1111/febs.17339","DOIUrl":null,"url":null,"abstract":"<p>Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that involves dopaminergic dysfunction in the prefrontal cortex (PFC), manifesting hyperactivity, inattention, and cognitive deficits. However, the ADHD-associated candidate genes underlying dopaminergic neurotransmission alterations remain poorly defined. Here, we identified the abundant localization of sodium-calcium exchanger 3 (NCX3) levels in the dopaminergic neurons of the ventral tegmental area, a major source of dopaminergic innervation to the PFC. We confirmed that NCX3 knockdown in N27 cells caused aberrant dopamine influx through the strong interaction between calcium/calmodulin-dependent protein kinase II alpha and dopamine transporter. In addition, we assessed behavioral changes and underlying molecular properties in NCX3 heterozygous (NCX3<sup>+/−</sup>) mice. NCX3<sup>+/−</sup> mice exhibited hyperactivity, cognitive deficits, and social dysfunction which were alleviated by treating with methylphenidate. Furthermore, NCX3<sup>+/−</sup> mice displayed a persistent elevation of basal dopamine levels and decreased extracellular levels of dopamine triggered by social stimuli in the PFC of NCX3<sup>+/−</sup> mice. In agreement with the rise in extracellular dopamine levels in the PFC, NCX3<sup>+/−</sup> mice showed activation of dopamine D1 receptor signaling pathways in the PFC compared to wild-type mice. Thus, deficiency of NCX3 leads to impaired dopaminergic neurotransmission in the PFC, which likely accounts for the ADHD-like behavior in NCX3<sup>+/−</sup> mice.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"292 2","pages":"426-444"},"PeriodicalIF":0.0000,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734882/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The FEBS journal","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/febs.17339","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that involves dopaminergic dysfunction in the prefrontal cortex (PFC), manifesting hyperactivity, inattention, and cognitive deficits. However, the ADHD-associated candidate genes underlying dopaminergic neurotransmission alterations remain poorly defined. Here, we identified the abundant localization of sodium-calcium exchanger 3 (NCX3) levels in the dopaminergic neurons of the ventral tegmental area, a major source of dopaminergic innervation to the PFC. We confirmed that NCX3 knockdown in N27 cells caused aberrant dopamine influx through the strong interaction between calcium/calmodulin-dependent protein kinase II alpha and dopamine transporter. In addition, we assessed behavioral changes and underlying molecular properties in NCX3 heterozygous (NCX3+/−) mice. NCX3+/− mice exhibited hyperactivity, cognitive deficits, and social dysfunction which were alleviated by treating with methylphenidate. Furthermore, NCX3+/− mice displayed a persistent elevation of basal dopamine levels and decreased extracellular levels of dopamine triggered by social stimuli in the PFC of NCX3+/− mice. In agreement with the rise in extracellular dopamine levels in the PFC, NCX3+/− mice showed activation of dopamine D1 receptor signaling pathways in the PFC compared to wild-type mice. Thus, deficiency of NCX3 leads to impaired dopaminergic neurotransmission in the PFC, which likely accounts for the ADHD-like behavior in NCX3+/− mice.

Abstract Image

在NCX3杂合小鼠中,前额皮质细胞外多巴胺清除异常表现出adhd样行为。
注意缺陷/多动障碍(ADHD)是一种涉及前额皮质(PFC)多巴胺能功能障碍的神经发育障碍,表现为多动、注意力不集中和认知缺陷。然而,与adhd相关的多巴胺能神经传递改变的候选基因仍然不明确。在这里,我们发现了钠钙交换器3 (NCX3)水平在腹侧被皮层的多巴胺能神经元中丰富的定位,这是多巴胺能神经支配的主要来源。我们证实了N27细胞中NCX3的敲低通过钙/钙调素依赖性蛋白激酶II α和多巴胺转运蛋白之间的强相互作用导致了异常的多巴胺流入。此外,我们评估了NCX3杂合(NCX3+/-)小鼠的行为变化和潜在的分子特性。NCX3+/-小鼠表现出多动症、认知缺陷和社交功能障碍,这些症状通过哌甲酯治疗得到缓解。此外,NCX3+/-小鼠的PFC中,社会刺激引发的基础多巴胺水平持续升高,细胞外多巴胺水平下降。与PFC细胞外多巴胺水平升高一致,与野生型小鼠相比,NCX3+/-小鼠在PFC中显示多巴胺D1受体信号通路的激活。因此,NCX3的缺乏导致PFC中多巴胺能神经传递受损,这可能是NCX3+/-小鼠adhd样行为的原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信