The Eye: A Window on Schizophrenia

描述(由申请人提供)： 这一研究项目旨在为揭示和研究精神疾病患者提供新的方法，特别是强调精神分裂症的根本原因。我们正在提出一种新的方法来评估精神分裂症患者，这种方法基于一种简单的眼科记录技术，称为视网膜电信号或ERG。ERG是一种常规的、非侵入性的从眼前部记录的电信号，是大多数眼科诊所的常见程序。我们认为，传统ERG的一种变体，称为模式ERG或PERG，反映了视网膜神经节细胞的活动，并具有特征反应成分，可归因于N-甲基-D-天冬氨酸或NMDA受体(NMDARs)的光诱导活性。NMDARs的异常调节被认为是精神分裂症的原因之一，该项目将最终评估这种可能性。事实上，我们已经获得了四名精神分裂症患者的初步数据，在这些患者中，PERG与正常对照组记录的PERG特征不同。当我们将精神分裂症患者的PERG与从隔离的、灌流的视网膜标本中记录的小鼠PERG进行比较时，小鼠的PERG看起来非常像对照组人类受试者，但当视网膜灌流一种拮抗剂来消除NMDA受体对PERG的贡献时，结果波形看起来与精神分裂症患者的PERG惊人地相似。这些显著的发现刺激了目前的应用，其广泛的目标是从更广泛的患者样本中进行记录，包括没有接受抗精神病药物治疗的精神分裂症患者，以确保我们在精神分裂症患者的PERG记录中没有观察到药物效果。这项研究背后的策略是使用PERG研究人类精神分裂症患者，并将他们与年龄和性别匹配的对照组进行比较。我们将通过测试程序评估每个人类受试者的认知功能，并在小鼠身上进行单独的实验，以确定NMDAR如何对PERG反应做出贡献。此外，我们计划进行实验，让小鼠在急性期和慢性期一直服用抗精神病药物。我们还将利用小鼠的准备来改进我们的PERG刺激参数，以优化NMDA受体的贡献，并相应地修改我们用于人类受试者的视觉刺激。我们期望这项研究将明确地解决精神分裂症患者中NMDA受体参与的问题。

DESCRIPTION (provided by applicant): This research project is designed to provide new methods for revealing and studying patients with psychiatric diseases with special emphasis on the root causes of schizophrenia. We are proposing a new way of evaluating schizophrenic patients based on a simple ophthalmological recording technique known as the electroretinogram or ERG. The ERG is an electrical signal routinely and non-invasively recorded from the front of the eye and is a common procedure found in most ophthalmological clinics. We propose that a variant of the conventional ERG, called the pattern ERG or pERG reflects activity of retinal ganglion cells and has a signature response component that can be attributed to light-evoked activity of N-methyl-D-Aspartate or NMDA receptors (NMDARs). Abnormal regulation of NMDARs has been implicated as one cause of schizophrenia and this project will definitively evaluate this possibility. Indeed, we hav obtained preliminary data from four schizophrenic patients in which the pERG is characteristically different than that recorded from normal controls. When we compare the schizophrenic pERG with the mouse pERG, recorded from an isolated, perfused retina preparation, the mouse pERG looks very much like the control human subjects, but when the retina is perfused with an antagonist that eliminates the contribution of NMDA receptors to the pERG, the resulting waveform looks strikingly similar to the pERG observed in schizophrenic patients. These remarkable findings have stimulated the current application, with the broad objective of recording from a wider sampling of patients, including schizophrenics that have not received anti-psychotic medication to insure that we are not observing a drug effect in pERG recordings from schizophrenic patients. The strategy behind this research is to use the pERG to study human patients with schizophrenia and compare them with age- and gender-matched controls. We will evaluate cognitive functions of each human subject through testing procedures and carry out separate experiments in mice to determine how NMDARs contribute to the pERG response. In addition, we plan to carry out experiments in which mice have been maintained on antipsychotic medication for acute and chronic periods. We will also use the mouse preparation to refine our pERG stimulation parameters to optimize for the NMDA receptor contribution and modify accordingly the visual stimulus we use for human subjects. We expect that this study will definitively address the question of NMDA receptor involvement in schizophrenic patients.