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.

项目总结

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