GABA and Early Intervention of Schizophrenia

GABA 与精神分裂症的早期干预

• 批准号: 7895794
• 负责人: TSUNG-UNG W. WOO
• 金额: $ 21.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895794
• 关键词: Adolescence; Adolescent; Age-Years; Aminobutyric Acids; Antipsychotic Agents; Attention; Attenuated; Autopsy; Back; Brain; Brief Psychiatric Rating Scale; Calcium-Binding Proteins; Cells; Clinical; Clinical Trials; Clozapine; Cognition; Cognitive; Cognitive deficits; Consensus; Data; Deterioration; Development; Dimensions; Disease; Double-Blind Method; Early treatment; Female; Functional disorder; Funding; GABA transporter; Gabitril; Generations; Goals; Human; Impaired cognition; Impairment; Injury; Intervention; Lead; Literature; Measurement; Measures; Mediating; Modification; Myoepithelial cell; Neurobehavioral Manifestations; Neurons; Onset of illness; Outcome Measure; Parvalbumins; Pathogenesis; Placebos; Play; Prefrontal Cortex; Prevention; Primates; Process; Psychotic Disorders; Pyramidal Cells; Randomized; Regimen; Reporting; Research; Role; Schedule; Schizophrenia; Short-Term Memory; Symptoms; Synapses; Synaptic Transmission; Testing; Therapeutic; Thinking; Time; Translating; Up-Regulation; base; cognitive function; early onset; emerging adult; excitotoxicity; gamma-Aminobutyric Acid; impression; improved; inhibitor/antagonist; male; neural circuit; neurotransmission; novel; pre-clinical; presynaptic; processing speed; public health relevance; research study; social cognition; tiagabine; translational approach

DESCRIPTION (provided by applicant): The overt symptoms and deficits of schizophrenia (SZ) typically begin to emerge during late adolescence and early adulthood, followed by a period of post-onset functional deterioration. This peri-onset period temporally coincides with the final maturation of the prefrontal cortex (PFC), which is characterized by a process of extensive pruning of synaptic connectivities. Increasing evidence suggests that upregulation of GABA neurotransmission, especially one that is mediated by the fast-spiking GABA cells that contain the calcium-binding protein parvalbumin (PV), which include the perisomatically targeting basket cells and the axo-axonic projecting chandelier cells, may play an important role in regulating the timing of the completion of peri-adolescent synaptic pruning. Interestingly, deficient PV neuronal functions and deficits of synaptic connectivities are increasingly recognized as key pathophysiologic features of SZ. Thus, there may be at least 2 mechanisms that may mediate the onset and early progression of SZ by contributing to PFC synaptic deficits: (1) Deficient GABA neurotransmission may prolong synaptic pruning, leading to excessive loss of synapses and (2) Reduced GABA inhibition may disinhibit pyramidal cells, making them prone to excitotoxic injury, which can be manifested as dendritic shrinkage and synaptic attrition. Thus, enhancement of GABA neurotransmission during the early course of SZ may, in the first scenario, normalize aberrant synaptic pruning and, in the second scenario, attenuate excitotoxicity-induced synaptic loss. In other words, GABA enhancement may restore the integrity of PFC neural circuits, which may then lead to lasting improvement in cognitive deficits and clinical symptoms. The proposed study will test this concept, focusing especially on working memory (WM), a key cognitive function mediated by the PFC. Thirty-six SZ subjects with onset of psychosis within 3 years, male or female, between 18-25 years of age, will be randomized to receive tiagabine (Gabitril), a selective inhibitor of the GABA transporter GAT-1, which may preferentially enhance GABA neurotransmission furnished by the PV-containing GABA cells during the peri-onset period, or placebo, added onto their regimen of second-generation antipsychotics, excluding clozapine. We will use a 2-back WM task and the WM sub-tests of the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) battery to assess possible improvement in WM. In addition, we will explore whether tiagabine may also improve positive and negative symptoms, as evaluated by clinical rating scales, and other aspects of cognition, including attention, processing speed, reasoning, and social cognition, as measured by tests in the MATRICS battery. This proof-of-concept study was conceptualized based on rather compelling preclinical data and may offer a completely new dimension in our thinking about the early intervention and prevention of SZ. PUBLIC HEALTH RELEVANCE The goal of this study is to test the hypothesis that enhancement of inhibitory neural transmission during the early course of schizophrenia may improve cognitive and symptomatic deficits.

描述（由申请人提供）：精神分裂症（SZ）的明显症状和缺陷通常在青春期和成年初期开始出现，随后发生了一段结束后的功能恶化。这个发发期限与前额叶皮层（PFC）的最终成熟相吻合，该过程的特征是突触连接性的广泛修剪过程。越来越多的证据表明，GABA神经传递的上调，尤其是由含有钙结合蛋白质白蛋白（PV）的快速加入的GABA细胞介导的，其中包括perisisemation靶向篮子细胞和Axo轴突轴突的投射枝条细胞，可能在调节该完整的综合元素中起重要作用。有趣的是，不足的PV神经元功能和突触连接性的缺陷越来越被认为是SZ的关键病理生理特征。 Thus, there may be at least 2 mechanisms that may mediate the onset and early progression of SZ by contributing to PFC synaptic deficits: (1) Deficient GABA neurotransmission may prolong synaptic pruning, leading to excessive loss of synapses and (2) Reduced GABA inhibition may disinhibit pyramidal cells, making them prone to excitotoxic injury, which can be manifested as树突状收缩和突触损耗。因此，在第一种情况下，在SZ早期过程中加剧神经传递的增强可能会使异常的突触修剪正常化，并且在第二种情况下，可以减轻兴奋性毒性诱导的突触损失。换句话说，GABA增强可能会恢复PFC神经回路的完整性，这可能会导致认知缺陷和临床症状的持续改善。拟议的研究将测试这一概念，特别关注工作记忆（WM），这是由PFC介导的关键认知功能。 Thirty-six SZ subjects with onset of psychosis within 3 years, male or female, between 18-25 years of age, will be randomized to receive tiagabine (Gabitril), a selective inhibitor of the GABA transporter GAT-1, which may preferentially enhance GABA neurotransmission furnished by the PV-containing GABA cells during the peri-onset period, or placebo, added onto their regimen of第二代抗精神病药，不包括氯氮平。我们将使用2退的WM任务以及基质的WM子测试（测量和治疗研究以改善精神分裂症的认知）电池，以评估WM的可能改善。此外，我们将探索tiagabine是否还可以通过临床评级量表以及认知的其他方面（包括注意力，加工速度，推理和社交认知）来评估，这是否还可以改善正症状和负面症状。这项概念验证研究是基于相当引人注目的临床前数据进行了概念化的，并且在我们对SZ的早期干预和预防的思考中可能会提供一个全新的维度。公共卫生相关性这项研究的目的是检验以下假设：在精神分裂症早期过程中，抑制性神经传播的增强可能会改善认知和症状缺陷。