GABA and Early Intervention of Schizophrenia

描述（由申请人提供）：精神分裂症（SZ）的显性症状和缺陷通常在青春期晚期和成年早期开始出现，随后是一段时间的发病后功能恶化。这一发病期在时间上与前额叶皮层（PFC）的最终成熟相一致，其特征是突触连接的广泛修剪过程。越来越多的证据表明，GABA神经传递的上调，特别是由含有钙结合蛋白小白蛋白（PV）的快速尖峰GABA细胞介导的上调，包括体周靶向篮状细胞和轴-轴突突出的枝形细胞，可能在调节青春期周围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越来越被认为是SZ的关键病理生理特征。因此，至少有2种机制可能通过促进PFC突触缺陷介导SZ的发生和早期进展：(1)GABA神经传递不足可延长突触修剪，导致突触过度丢失；(2)GABA抑制减弱可解除锥体细胞的抑制，使其容易发生兴奋性毒性损伤，表现为树突萎缩和突触磨损。因此，在SZ早期过程中，GABA神经传递的增强，在第一种情况下，可能使异常突触修剪正常化，在第二种情况下，可能减弱兴奋毒性诱导的突触丧失。换句话说，GABA增强可能会恢复PFC神经回路的完整性，从而导致认知缺陷和临床症状的持续改善。该研究将测试这一概念，尤其关注工作记忆（WM），这是一种由pfa介导的关键认知功能。36名SZ患者在3年内发病，男性或女性，年龄在18-25岁之间，将随机接受替加滨（Gabitril），一种GABA转运体GAT-1的选择性抑制剂，可优先增强发作期由含pv的GABA细胞提供的GABA神经传递，或安慰剂。加上第二代抗精神病药物，氯氮平除外。我们将使用双回WM任务和matrix（改善精神分裂症认知的测量和治疗研究）的WM子测试来评估WM可能的改善。此外，我们将探讨地加滨是否也可以改善阳性和阴性症状（通过临床评定量表评估），以及其他方面的认知，包括注意力、处理速度、推理和社会认知（通过matrix电池测试测量）。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概念化的，可能会为我们对SZ的早期干预和预防提供一个全新的视角。本研究的目的是验证在精神分裂症早期过程中增强抑制性神经传递可能改善认知和症状性缺陷的假设。

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.