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晚期和成年期早期，随后是一段发病后的功能退化时期。这一起病前期在时间上与前额叶皮质(PFC)的最终成熟相吻合，PFC的特征是突触连接的广泛修剪过程。越来越多的证据表明，GABA神经递质的上调，特别是由含有钙结合蛋白小白蛋白(PV)的快峰GABA细胞介导的上调，可能在调节青春期前突触修剪完成的时间方面发挥重要作用。有趣的是，PV神经元功能缺陷和突触连接缺陷日益被认为是SZ的关键病理生理特征。因此，至少有两种机制可能通过导致PFC突触缺陷来介导SZ的发生和早期发展：(1)GABA神经传递缺陷可能延长突触修剪，导致突触过度丢失；(2)GABA抑制减少可能抑制锥体细胞，使其容易受到兴奋性损伤，表现为树突萎缩和突触磨损。因此，在SZ早期，GABA神经传递的增强可能在第一种情况下使异常突触修剪正常化，在第二种情况下减轻兴奋性毒性诱导的突触丢失。换句话说，增强GABA可能会恢复PFC神经回路的完整性，这可能会导致认知障碍和临床症状的持久改善。这项拟议的研究将测试这一概念，特别是关注工作记忆(WM)，这是一种由PFC调节的关键认知功能。36名在3年内出现精神病的SZ受试者，男性或女性，年龄在18-25岁之间，将被随机分成两组，一组接受GABA转运体GAT-1的选择性抑制剂替加他滨(Gabitril)，该药物可能优先增强发作期内含PV的GABA细胞提供的GABA神经传递，或在他们的第二代抗精神病药物(不包括氯氮平)方案中添加安慰剂。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可能的改善。此外，我们还将探讨替加宾是否也可以改善临床评定量表所评估的阳性和阴性症状，以及Matrics电池测试所衡量的其他认知方面，包括注意力、处理速度、推理和社会认知。这项概念验证研究是基于相当令人信服的临床前数据而概念化的，可能为我们思考SZ的早期干预和预防提供了一个全新的维度。公共卫生相关性这项研究的目的是检验这一假设，即在精神分裂症早期加强抑制性神经传递可能会改善认知和症状障碍。

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.