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

精神分裂症最一致和最具重复性的尸检发现之一是 编码67kD谷氨酸脱羧酶(GAD67)亚型的mRNA，主要是该酶 负责GABA的合成。该中心的一个中心假设是，GABA中的干扰 神经传递在精神分裂症患者的信息处理障碍中起着关键作用。 这些损害代表了精神分裂症的一个显著和致残的特征，并强烈预测了 功能结果。因此，理解认知的病理生理机制 损伤已经成为开发治疗这种疾病的新疗法的关键焦点。然而，为了 到目前为止，没有直接的体内证据表明精神分裂症患者的GABA功能发生了变化，或者GABA 在尸检中观察到的异常与这种疾病的功能障碍有关。 因此，该项目的目标是开发和验证一种方法学，用于在体内探索 有证据表明，GABA传递在大脑皮质区域广泛受损，在患有 精神分裂症。该项目将(1)验证使用[11C]氟马西尼PET来检测细胞外的变化 服用替加宾(一种抑制GABA再摄取的药物)后的GABA水平 阻断GABA转运体，GAT1)和(2)检测替加宾诱导的GABA水平的变化 首发、抗精神病药NATVE、精神分裂症受试者(Fan-S)与 健康对照组。我们预测精神分裂症将与增加的能力缺陷有关 使用正电子发射计算机断层扫描，体内测量时，细胞外GABA水平对替加宾的反应。所有受试者都将 参与项目4-Phillips，该项目将创建一个允许我们探索存在的多模式数据集 该中心的总体模型所预测的一系列关系。我们将测试假设，在 Fan-S受试者，缺乏增加GABA水平的能力，表现为迟钝的改变 [11C]替加宾对氟马西尼的结合反应与伽马振荡活动受损有关 通过EEC测量，在认知控制任务期间，fMRI BOLD信号减少，并且 认知障碍将与提高GABA水平的能力成反比。这个项目将 提供项目1-Lewis的尸检研究与 项目4--菲利普斯。这将使我们能够直接测试GABA传递减少的假设 精神分裂症(项目1-Lewis)，并结合项目4-Phillips的数据确定是否减少 GABA与体内观察到的振荡和功能磁共振干扰有关。开发的方法 通过这个项目将提供一个创新的生物标记物，可以用来监测新的效果 精神分裂症的治疗药物。

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.