The Eye: A Window on Schizophrenia

描述（由申请人提供）： 该研究项目旨在提供新的方法来揭示和研究精神病患者，特别强调精神分裂症的根本原因。我们提出了一种新的方法来评估精神分裂症患者的基础上，一个简单的眼科记录技术称为视网膜电图或ERG。ERG是从眼睛前部常规且非侵入性地记录的电信号，并且是在大多数眼科诊所中发现的常见程序。我们提出，一个变种的传统的ERG，称为模式ERG或pERG反映视网膜神经节细胞的活动，并有一个签名响应组件，可以归因于光诱发的活动N-甲基-D-天冬氨酸或NMDA受体（NMDARs）。NMDAR的异常调节被认为是精神分裂症的原因之一，本项目将明确评估这种可能性。实际上，我们已经从4例精神分裂症患者中获得了初步数据，这些患者的pERG与正常对照组的pERG有特征性的不同。当我们将精神分裂症患者的pERG与小鼠的pERG进行比较时，从分离的灌注视网膜制备物中记录的小鼠pERG看起来非常像对照人类受试者，但是当视网膜灌注有消除NMDA受体对pERG的贡献的拮抗剂时，所得波形看起来与精神分裂症患者中观察到的pERG惊人地相似。这些显著的发现刺激了当前的应用，其广泛的目标是从更广泛的患者样本中记录，包括未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作用。这项研究背后的策略是使用pERG来研究精神分裂症患者，并将其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，并在小鼠中进行单独的实验，以确定NMDAR如何促进pERG反应。此外，我们计划进行实验，在这些实验中，小鼠在急性期和慢性期一直服用抗精神病药物。我们还将使用小鼠制备物来完善我们的pERG刺激参数，以优化NMDA受体的作用，并相应地修改我们用于人类受试者的视觉刺激。我们希望这项研究将明确解决精神分裂症患者的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.