GABA and Early Intervention of Schizophrenia

描述（由申请人提供）：精神分裂症（SZ）的明显症状和缺陷通常开始出现在青春期后期和成年早期，随后是一段时间的发病后功能恶化。这一发病前后的时期在时间上与前额叶皮层（PFC）的最终成熟相吻合，其特征在于突触连接的广泛修剪过程。越来越多的证据表明，GABA神经传递的上调，特别是一个由快速尖峰GABA细胞介导的钙结合蛋白小白蛋白（PV），其中包括perisomatically靶向篮状细胞和轴-轴投射枝形细胞，可能在调节青春期突触修剪完成的时间发挥重要作用。有趣的是，PV神经元功能缺陷和突触连接缺陷越来越多地被认为是SZ的关键病理生理特征。因此，可能存在至少2种机制可通过促成PFC突触缺陷来介导SZ的发作和早期进展：（1）缺乏GABA神经传递可延长突触修剪，导致突触过度损失，以及（2）减少的GABA抑制可解除对锥体细胞的抑制，使其易于发生兴奋性毒性损伤，其可表现为树突收缩和突触磨损。因此，在SZ的早期过程中的GABA神经传递的增强，在第一种情况下，正常化异常突触修剪，在第二种情况下，衰减兴奋性毒性诱导的突触丢失。换句话说，GABA增强可能会恢复PFC神经回路的完整性，从而可能导致认知缺陷和临床症状的持久改善。拟开展的研究将检验这一概念，尤其侧重于工作记忆（WM），这是PFC介导的一种关键认知功能。36名SZ受试者在3年内发生精神病，男性或女性，年龄在18 - 25岁之间，将随机接受噻加宾治疗（Gabitril），GABA转运蛋白GAT-1的选择性抑制剂，其可以优先增强由在发病前期期间的含PV的GABA细胞提供的GABA神经传递，或安慰剂，添加到其第二代抗精神病药（不包括氯氮平）的方案中。我们将使用2-back WM任务和MATRICS（改善精神分裂症认知的测量和治疗研究）电池的WM子测试来评估WM的可能改善。此外，我们将探讨噻加宾是否也可以改善阳性和阴性症状，通过临床评定量表进行评估，以及认知的其他方面，包括注意力，处理速度，推理和社会认知，通过MATRICS电池测试进行测量。这项概念验证研究是基于相当令人信服的临床前数据概念化的，可能为我们对SZ早期干预和预防的思考提供一个全新的维度。公共卫生相关性本研究的目的是检验这一假设，即在精神分裂症的早期过程中，抑制性神经传递的增强可能改善认知和症状缺陷。

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.