Investigation of EAAT3 in OCD Pathophysiology

项目总结 强迫症(OCD)是最具致残性的慢性精神障碍之一，具有 终生患病率为2-3%。新的发现表明，基底神经节回路在强迫症中起着重要作用。 尽管如此，我们对强迫症的分子病理生理学的了解仍然不够，我们的 治疗方案使大多数患者持续受损。在强迫症中复制最好的基因发现是 与SLC1A1结合，编码神经元谷氨酸、天冬氨酸和半胱氨酸转运蛋白 EAAT3/EAAC1。然而，该基因对强迫症相关的正常和异常功能的影响 电路是未知的。为了填补这一知识空白，我们开发了Stop-Teto敲入鼠标系列，使我们能够 灵活操作Slc1a1表达式。使用多巴胺激动剂作为探针，我们发现EAAT3丢失 减少基底节介导的重复的、刻板的行为。我们的融合数据支持 假设EAAT3功能增强在强迫症的病理中起作用，而EAAT3活性降低 可作为一种新的治疗选择。然而，人们对EAT3的S的分子和功能知之甚少 对基底节的影响。在大脑的其他地方，EAAT3介导的运输减少了神经传递 在突触周围的谷氨酸受体，并为GABA和谷胱甘肽的合成提供底物，但它 不清楚这些功能中的哪些在基底节回路中是重要的，也不清楚EAAT3对S的影响 多巴胺能神经传递是突触前或突触后的。使用我们灵活的鼠标模型和以前的 建立了强迫症光遗传和转基因小鼠模型，本R01将1)检测EAAT3的作用 消融和靶向抢救对基底节功能和重复行为的影响；2)确定EAAT3 消融导致表型相似但病因学无关的小鼠模型的症状缓解 基底节信号异常的强迫症。这些数据可以被用来证明一种明确的处理方法 激励开发前景看好的EAAT3抑制剂先导化合物的目标。

PROJECT SUMMARY Obsessive-compulsive disorder (OCD) is one of the most disabling, chronic psychiatric disorders, with a lifetime prevalence of 2-3%. Emerging findings point to a significant role for basal ganglia circuits in OCD. Despite this, our understanding of the molecular pathophysiology of OCD remains inadequate, and our treatment options leave most patients with continued impairment. The best-replicated genetic finding in OCD is association with SLC1A1, encoding the neuronal glutamate, aspartate, and cysteine transporter EAAT3/EAAC1. However, the impact of this gene on the normal and abnormal functioning of OCD-related circuits is unknown. To fill this knowledge gap, we developed a STOP-TetO knock-in mouse line that allows us to flexibly manipulate Slc1a1 expression. Using dopamine agonists as a probe, we found that EAAT3 loss decreases basal ganglia-mediated repetitive, stereotyped behavior. Our convergent data support the hypothesis that increased EAAT3 function plays a role in OCD pathology and that decreasing EAAT3 activity may serve as a novel treatment option. Little is known, however, about EAAT3's molecular and functional impact in the basal ganglia. Elsewhere in the brain, EAAT3-mediated transport decreases neurotransmission at perisynaptic glutamate receptors and provides substrate for GABA and glutathione synthesis, but it is unclear which of these functions is important in basal ganglia circuits, and whether EAAT3's impact on dopaminergic neurotransmission is pre- or post-synaptic. Using our flexible mouse model and previously established OCD optogenetic and transgenic mouse models, this R01 will 1) examine effects of EAAT3 ablation and targeted rescue on basal ganglia function and repetitive behavior, and 2) determine if EAAT3 ablation leads to symptom resolution in phenotypically-similar but etiologically-independent mouse models of OCD with abnormal basal ganglia signaling. These data could be leveraged to demonstrate a clear treatment target that motivates development of promising EAAT3 inhibitor lead compounds.