Vanderbilt University Brain Institute, Nashville, Tennessee, USA.
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
J Clin Invest. 2019 May 16;129(8):3407-3419. doi: 10.1172/JCI127411.
The precise regulation of synaptic dopamine (DA) content by the dopamine transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions to the DA system are implicated in a number of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and, more recently, Autism Spectrum Disorder (ASD). An ASD-associated de novo mutation in the SLC6A3 gene resulting in a threonine to methionine substitution at site 356 (DAT T356M) was recently identified and has been shown to drive persistent reverse transport of DA (i.e. anomalous DA efflux) in transfected cells and to drive hyperlocomotion in Drosophila melanogaster. A corresponding mutation in the leucine transporter, a DAT-homologous transporter, promotes an outward-facing transporter conformation upon substrate binding, a conformation possibly underlying anomalous dopamine efflux. Here we investigated in vivo the impact of this ASD-associated mutation on DA signaling and ASD-associated behaviors. We found that mice homozygous for this mutation display impaired striatal DA neurotransmission and altered DA-dependent behaviors that correspond with some of the behavioral phenotypes observed in ASD.
多巴胺转运体（DAT）精确调节突触多巴胺（DA）含量，确保了 DA 信号的脉冲性质，这是 DA 编码奖励预测误差的基础，从而驱动动机、注意力和行为学习。DA 系统的紊乱与许多神经精神疾病有关，包括注意缺陷多动障碍（ADHD），最近还与自闭症谱系障碍（ASD）有关。最近在 SLC6A3 基因中发现了一个与 ASD 相关的从头突变，导致第 356 位苏氨酸突变为蛋氨酸（DAT T356M），该突变已被证明可在转染细胞中驱动持续的反向转运 DA（即异常 DA 外排），并驱动黑腹果蝇的过度运动。在亮氨酸转运体（一种 DAT 同源转运体）中相应的突变促进了底物结合时向外的转运体构象，这种构象可能是异常多巴胺外排的基础。在这里，我们研究了这种与 ASD 相关的突变对 DA 信号和与 ASD 相关的行为的体内影响。我们发现，这种突变的纯合子小鼠表现出纹状体 DA 神经传递受损和 DA 依赖性行为改变，与 ASD 中观察到的一些行为表型相对应。
