Investigation of EAAT3 in OCD Pathophysiology

EAAT3 在 OCD 病理生理学中的研究

• 批准号: 10203778
• 负责人: Susanne Elizabeth Ahmari
• 金额: $ 51.9万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203778
• 关键词: Ablation; Adult; Affect; Agonist; Amphetamines; Animals; Aspartate; Attenuated; Basal Ganglia; Behavior; Behavioral; Brain; Chronic; Corpus striatum structure; Cre driver; Cysteine; Data; Development; Disease; Dopamine; Dopamine Agonists; Etiology; Functional disorder; Genes; Genetic; Genetic Crosses; Genetic Models; Genetic study; Glutamate Receptor; Glutamates; Glutathione; Goals; Grooming; Human; Hyperactivity; Impairment; Injections; Investigation; Knock-in Mouse; Knockout Mice; Knowledge; Lead; Link; Mediating; Mental disorders; Microdialysis; Midbrain structure; Modeling; Molecular; Mus; Neurons; Obsessive-Compulsive Disorder; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physiology; Play; Population; Prevalence; Resolution; Role; Signal Transduction; Specificity; Stereotyped Behavior; Stereotyping; Symptoms; Synapses; System; Technology; Testing; Transgenic Mice; Viral; Work; amphetamine use; base; cell type; dopaminergic neuron; effective therapy; excitatory amino acid transporter 3; flexibility; gamma-Aminobutyric Acid; genetic manipulation; in vivo; inhibitor/antagonist; microendoscopy; mouse model; neurotransmission; novel; optogenetics; overexpression; repetitive behavior; response; restoration; theories; therapeutic target

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.

项目摘要 强迫症（OCD）是最残疾，慢性精神病患者之一， 终身患病率为2-3％。新兴发现表明基底神经节电路在强迫症中发挥了重要作用。 尽管如此，我们对OCD分子病理生理学的理解仍然不足，我们的 治疗选择使大多数患者持续损害。 OCD中最佳遗传发现是 与SLC1A1相关，编码神经元谷氨酸，天冬氨酸和半胱氨酸转运蛋白 EAAT3/EAAC1。但是，该基因对OCD相关的正常和异常功能的影响 电路是未知的。为了填补这一知识差距，我们开发了一条停止的敲门鼠标线，使我们允许我们 灵活地操纵SLC1A1表达。使用多巴胺激动剂作为探针，我们发现EAAT3损失 减少基底神经节介导的重复，定型的行为。我们的收敛数据支持 增加EAAT3功能的假设在OCD病理学中起作用，并且降低了EAAT3活性 可以用作新的治疗选择。然而，关于EAAT3的分子和功能鲜为人知 在基底神经节上的影响。在大脑的其他地方，EAAT3介导的运输会减少神经传递 在酸性谷氨酸受体上，为GABA和谷胱甘肽合成提供底物，但它是 不清楚这些功能中的哪一个在基底神经节电路中很重要，以及EAAT3是否对 多巴胺能神经传递是前或突触后的。使用我们的灵活鼠标模型和以前 已建立的OCD OCD光遗传学和转基因小鼠模型，此R01将1）检查EAAT3的效果 消融和针对基础神经节功能和重复行为的目标营救，2）确定EAAT3是否是否 消融导致表型相似但病因独立的小鼠模型的症状解决 OCD具有异常基底神经节信号传导。可以利用这些数据来证明明确的处理 促进有希望的EAAT3抑制剂铅化合物的目标。

项目成果

Neuronal excitatory amino acid transporter EAAT3: Emerging functions in health and disease.

• DOI: 10.1016/j.neuint.2018.05.012
• 发表时间: 2019-03
• 期刊: Neurochemistry international
• 影响因子: 4.2
• 作者: Underhill SM;Ingram SL;Ahmari SE;Veenstra-VanderWeele J;Amara SG
• 通讯作者: Amara SG

Altered baseline and amphetamine-mediated behavioral profiles in dopamine transporter Cre (DAT-Ires-Cre) mice compared to tyrosine hydroxylase Cre (TH-Cre) mice.

• DOI: 10.1007/s00213-020-05635-4
• 发表时间: 2020-12
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Chohan, Muhammad O.;Esses, Sari;Haft, Julia;Ahmari, Susanne;Veenstra-VanderWeele, Jeremy
• 通讯作者: Veenstra-VanderWeele, Jeremy