Project 5: In vivo measurement of GABA transmission in healthy controls & subject

项目 5：健​​康对照中 GABA 传输的体内测量

• 批准号: 8279481
• 负责人: CHESTER A MATHIS
• 金额: $ 27.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8279481
• 关键词: Address; Anesthesia procedures; Antipsychotic Agents; Autopsy; Binding; Biological Markers; Brain region; Cerebral cortex; Clinical Research; Data; Data Set; Development; Dose; Electroencephalography; Feedback; Flumazenil; Functional Magnetic Resonance Imaging; GABA transporter; GAD67 enzyme; Glutamate Decarboxylase; Goals; Impaired cognition; Impairment; Individual; Link; Measurement; Measures; Methodology; Methods; Microdialysis; Modeling; Monitor; Neuropsychological Tests; Occipital lobe; Oral Administration; Outcome Measure; Pharmaceutical Preparations; Play; Positron-Emission Tomography; Protein Isoforms; Radiation; Recruitment Activity; Relative (related person); Reproducibility; Schizophrenia; Sensory; Short-Term Memory; Signal Transduction; Temporal Lobe; Testing; Time; Validation; base; cognitive control; extracellular; functional disability; functional outcomes; gamma-Aminobutyric Acid; in vivo; information processing; innovation; mRNA Expression; neurotransmission; nonhuman primate; novel therapeutics; research clinical testing; response; reuptake; tiagabine; transmission process

One of the most consistent and replicated postmortem findings in schizophrenia is the reduced expression of the mRNA encoding the 67 kD isoform of glutamic acid decarboxylase (GAD67), the enzyme principally responsible for the synthesis of GABA. A central hypothesis of the Center is that disturbances in GABA neurotransmission play a key role in the information processing impairments observed in schizophrenia. These impairments represent a prominent and disabling feature of schizophrenia and a strong predictor of functional outcome. Thus, understanding the pathophysiologic mechanisms underlying cognitive impairments has become a critical focus in the development of novel therapeutics for the illness. However, to date, there is no direct, in vivo evidence that GABA function is altered in schizophrenia or that the GABA abnormalities observed in postmortem studies are linked to functional impairments in this illness. Consequently, the goal of this project is to develop and validate a methodology for exploring, in vivo, the evidence that GABA transmission is broadly impaired, across cortical brain regions, in subjects with schizophrenia. This project will (1) validate the use of [11C]flumazenil PET to detect changes in extracellular GABA levels resulting from the administration of tiagabine (a drug which inhibits the reuptake of GABA by blocking the GABA transporter, GAT1) and (2) examine tiagabine-induced changes in GABA levels in cortical regions in first-episode, antipsychotic-naTve, schizophrenia subjects (FEAN-S) compared with healthy controls. We predict that schizophrenia will be associated with a deficit in the ability to increase extracellular GABA levels in response to tiagabine when measured in vivo, using PET. All subjects will participate in Project 4-Phillips which will create a multi-modal dataset permitting us to explore the existence of a number of relationships predicted by the overall model of this Center. We will test the hypothesis that, in FEAN-S subjects, deficits in the ability to increase GABA levels, as indicated by blunting of the change in [11C]flumazenil binding in response to tiagabine, will be associated with impaired gamma oscillatory activity as measured by EEC, and decreased fMRI BOLD signal, during a cognitive control task, and that the level of cognitive impairment will be inversely correlated with the ability to increase GABA levels. This project will provide a key link between the postmortem studies of Project 1-Lewis and the clinical studies outlined in Project 4-Phillips. It will allow us to directly test the hypothesis that GABA transmission is reduced in schizophrenia (Project 1-Lewis) and, in combination with data from Project 4-Phillips, determine if reduced GABA is associated with the oscillation and fMRI disturbances observed in vivo. The methods developed through this project will thus provide a innovative biomarker that can be used to monitor the effects of novel therapeutic drugs in schizophrenia.

精神分裂症中最一致和重复的死后发现之一是 编码谷氨酸脱羧酶（GAD 67）的67 kD亚型的mRNA，该酶主要 负责合成GABA。该中心的一个核心假设是， 神经传递在精神分裂症中观察到的信息处理损伤中起关键作用。 这些损伤代表了精神分裂症的一个突出和致残的特征，并且是精神分裂症的一个强有力的预测因子。 功能性成果。因此，了解认知障碍的病理生理机制， 损伤已经成为开发用于该疾病的新疗法的关键焦点。但要 迄今为止，没有直接的体内证据表明GABA功能在精神分裂症中改变，或者GABA 尸检中观察到的异常与这种疾病的功能障碍有关。 因此，本项目的目标是开发和验证一种方法，用于探索，在体内， 有证据表明，GABA的传递在大脑皮层区域广泛受损，在受试者中， 精神分裂症本项目将（1）验证使用[11 C]氟马西尼PET检测细胞外 由给予噻加宾（一种通过抑制GABA再摄取的药物）引起的GABA水平 阻断GABA转运蛋白，GAT 1）和（2）检查在小鼠中的GABA水平的噻加宾诱导的变化。 首次发作，抗精神病药初治，精神分裂症受试者（FEAN-S）的皮层区域与 健康对照我们预测，精神分裂症将与一个赤字的能力，增加 当使用PET在体内测量时，响应于噻加宾的细胞外GABA水平。所有受试者将 我参加了项目4-菲利普斯，这将创建一个多模态数据集，使我们能够探索的存在 这个中心的整体模型所预测的一些关系。我们将测试假设，在 FEAN-S受试者，增加GABA水平的能力不足，如通过减少GABA水平的变化所指示的。 [11 C]氟马西尼结合对噻加宾的反应，将与受损的γ振荡活性相关 在认知控制任务中，通过EEC测量，并降低fMRI BOLD信号，并且 认知障碍将与增加GABA水平的能力负相关。该项目将 在项目1-刘易斯的尸检研究和 项目4-菲利普斯。这将使我们能够直接测试GABA传输减少的假设， 精神分裂症（项目1-刘易斯），并结合项目4-菲利普斯的数据，确定是否减少 GABA与体内观察到的振荡和fMRI干扰有关。开发的方法 因此，通过该项目将提供一种创新的生物标志物，可用于监测新的 精神分裂症的治疗药物