Investigation of EAAT3 in OCD Pathophysiology

EAAT3 在 OCD 病理生理学中的研究

基本信息

批准号：
9511919
负责人：
Susanne Elizabeth Ahmari
金额：
$ 53.7万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9511919
关键词：
Ablation Adult Affect Agonist Amphetamines Animals Aspartate Attenuated Basal Ganglia Behavior Behavioral Brain Chronic Corpus striatum structure Cysteine Data Development Disease Dopamine Dopamine Agonists EAAT3 Etiology Functional disorder Genes Genetic Genetic Crosses Genetic Models Genetic study Glutamate Receptor Glutamates Glutathione Goals Grooming Human Hyperactive behavior 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 flexibility gamma-Aminobutyric Acid genetic manipulation in vivo inhibitor/antagonist microendoscopy mouse model neurotransmission novel optogenetics overexpression repetitive behavior response restoration theories therapeutic target

项目摘要

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.

项目概要强迫症 (OCD) 是最致残的慢性精神疾病之一，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发挥着重要作用。尽管如此，我们对强迫症分子病理生理学的理解仍然不足，我们的研究治疗选择使大多数患者持续受到损害。强迫症中最可复制的遗传发现是与 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。然而，该基因对强迫症相关的正常和异常功能的影响电路未知。为了填补这一知识空白，我们开发了 STOP-TetO 敲入小鼠系列，使我们能够灵活操纵Slc1a1表达。使用多巴胺激动剂作为探针，我们发现 EAAT3 丢失减少基底神经节介导的重复、刻板行为。我们的融合数据支持假设 EAAT3 功能增加在强迫症病理学中发挥作用，而 EAAT3 活性降低可能作为一种新的治疗选择。然而，人们对 EAAT3 的分子和功能知之甚少。对基底神经节的影响。在大脑的其他地方，EAAT3 介导的运输会减少神经传递位于突触周围谷氨酸受体并为 GABA 和谷胱甘肽合成提供底物，但它不清楚这些功能中的哪一个在基底神经节回路中很重要，以及 EAAT3 是否对多巴胺能神经传递位于突触前或突触后。使用我们灵活的鼠标模型和之前的模型建立了 OCD 光遗传学和转基因小鼠模型，此 R01 将 1) 检查 EAAT3 的效果对基底神经节功能和重复行为进行消融和针对性救援，2) 确定 EAAT3 是否消融导致表型相似但病因独立的小鼠模型的症状消退基底神经节信号传导异常的强迫症。这些数据可以用来证明明确的治疗方法刺激开发有前景的 EAAT3 抑制剂先导化合物的目标。