Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model.
Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model.
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DOI：
10.1186/s11689-017-9215-8
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发表时间：
2017-12-28
影响因子：
4.9
通讯作者：
McMahon DG
中科院分区：
文献类型：
--
作者：
Dai H;Jackson CR;Davis GL;Blakely RD;McMahon DG
多巴胺（DA）是视网膜中的重要神经调质。视网膜DA合成和信号传导的中断显著减弱光适应、视网膜电图（ERG）反应以及对比敏感度和敏锐度。由于这些措施可以非侵入性地检测，它们可能提供机会来检测与扰动的DA信号传导相关的疾病过程。最近，我们发现了一种罕见的，功能性DA转运蛋白（DAT，SLC 6A 3）编码取代，Ala 559 Val，在注意力缺陷/多动障碍（ADHD）的主题，证明DAT Val 559赋予异常DA流出（ADE）伴随的生理，药理学和行为表型。为了了解ADE对ADHD的更广泛影响，需要对DAT逆转敏感的非侵入性措施。在这里，我们通过基于ERG的视网膜光反应分析以及DAT Val 559小鼠视网膜DA的HPLC测量来探索这个问题。与野生型（WT）和杂合型（HET）小鼠相比，DAT Val 559变体纯合型（HOM）雄性小鼠表现出增加的光适应ERG b波振幅，而暗适应反应在不同基因型之间无法区分。HOM小鼠中明视光反应幅度的升高可通过应用D1和D4 DA受体激动剂在WT小鼠中模拟，并通过引入D4拮抗剂在HOM小鼠中抑制，支持ADE引起的视网膜DA信号传导升高。在用安非他明攻击后，WT表现出光适应反应幅度的增加，而HOM没有。视网膜总DA含量在各基因型间相似。有趣的是，当与WT和HET同窝仔相比时，雌性DAT Val 559 HOM动物在明视ERG反应方面没有显示出显著差异。这些数据表明，非侵入性的，在体内评价视网膜对光的反应，可以揭示生理特征的ADE，这表明一种可能的方法来隔离的神经行为障碍的基础上的DAT依赖性控制DA信号。
Dopamine (DA) is a critical neuromodulator in the retina. Disruption of retinal DA synthesis and signaling significantly attenuates light-adapted, electroretinogram (ERG) responses, as well as contrast sensitivity and acuity. As these measures can be detected noninvasively, they may provide opportunities to detect disease processes linked to perturbed DA signaling. Recently, we identified a rare, functional DA transporter (DAT, SLC6A3) coding substitution, Ala559Val, in subjects with attention-deficit/hyperactivity disorder (ADHD), demonstrating that DAT Val559 imparts anomalous DA efflux (ADE) with attendant physiological, pharmacological, and behavioral phenotypes. To understand the broader impact of ADE on ADHD, noninvasive measures sensitive to DAT reversal are needed. Here, we explored this question through ERG-based analysis of retinal light responses, as well as HPLC measurements of retinal DA in DAT Val559 mice. Male mice homozygous (HOM) for the DAT Val559 variant demonstrated increased, light-adapted ERG b-wave amplitudes compared to wild type (WT) and heterozygous (HET) mice, whereas dark-adapted responses were indistinguishable across genotypes. The elevated amplitude of the photopic light responses in HOM mice could be mimicked in WT mice by applying D1 and D4 DA receptor agonists and suppressed in HOM mice by introducing D4 antagonist, supporting elevated retinal DA signaling arising from ADE. Following the challenge with amphetamine, WT exhibited an increase in light-adapted response amplitudes, while HOM did not. Total retinal DA content was similar across genotypes. Interestingly, female DAT Val559 HOM animals revealed no significant difference in photopic ERG responses when compared with WT and HET littermates. These data reveal that noninvasive, in vivo evaluation of retinal responses to light can reveal physiological signatures of ADE, suggesting a possible approach to the segregation of neurobehavioral disorders based on the DAT-dependent control of DA signaling.
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DOI：
10.1523/jneurosci.5094-09.2010
发表时间：
2010-04-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bowton E;Saunders C;Erreger K;Sakrikar D;Matthies HJ;Sen N;Jessen T;Colbran RJ;Caron MG;Javitch JA;Blakely RD;Galli A
通讯作者：
Galli A
影响因子：
4.9
作者：
de Graaf, R.;Kessler, R. C.;Posada-Villa, J.
通讯作者：
Posada-Villa, J.
影响因子：
5
作者：
DIPAOLO, T;ROUILLARD, C;BEDARD, P
通讯作者：
BEDARD, P
影响因子：
8
作者：
Biederman, J;Lopez, FA;Chandler, MC
通讯作者：
Chandler, MC
影响因子：
1.7
作者：
Cheng, Zhe;Zhong, Yong-Mei;Yang, Xiong-Li
通讯作者：
Yang, Xiong-Li