pERG of Schizophrenia

精神分裂症的 pERG

• 批准号: 8836326
• 负责人: Nathalia Torres Jimenez
• 金额: $ 3.66万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836326
• 关键词: AMPA Receptors; Accounting; Address; Affect; Agonist; American; Animals; Antipsychotic Agents; Behavioral; Binding; Brain; Caring; Cell physiology; Chronic; Chronic Disease; Clinical; Clinical Research; Communication; Cornea; Data; Diagnosis; Diagnostic; Disease; Dissociative Anesthetics; Economic Burden; Electrodes; Electroretinography; Emotional; Etiology; Eye; Genetic Predisposition to Disease; Glutamate Receptor; Glutamates; Goals; Human; Image; Impaired cognition; In Vitro; Knowledge; Light; Masks; Measures; Mediating; Medical; Monitor; Mouse Strains; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; National Institute of Mental Health; Neurotransmitters; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Population; Preparation; Prevention; Procedures; Public Health; Receptor Activation; Regulation; Relative (related person); Research; Research Project Grants; Retina; Retinal Ganglion Cells; Schizophrenia; Serine; Signal Transduction; Stimulus; Strategic Planning; Symptoms; Synapses; System; Techniques; Testing; Variant; cost; extracellular; ganglion cell; improved; mouse model; mutant; public health relevance; receptor function; recreational drug use; response; tool

DESCRIPTION (provided by applicant): Schizophrenia is a chronic disruptive disease that affects 1% of the population. Current treatment only relieves symptoms but does not cure the disease. Unfortunately, the exact cause of schizophrenia is not known. Throughout the years there have been multiple hypotheses for schizophrenia, one of which arrived from clinical studies of dissociative anesthetics that imitate the negative symptoms (disruption to emotional and behavioral states), cognitive impairments, and brain abnormalities associated with schizophrenia. Since these dissociative anesthetics antagonize a subclass of glutamate receptors called NMDA receptors, it is postulated that like the drugs, schizophrenia results from hypoactivity of the NMDA receptor. Interestingly, some schizophrenic patients have a deficiency of D-serine, a co-agonist of the NMDA receptor. When treated with D-serine, schizophrenic symptoms improve. By using a variation of the electroretinogram (ERG), known as the pattern- ERG, or pERG, we can measure NMDA-mediated activity that is evoked by light in retinal ganglion cells. This application seeks to understand how different levels of D-serine determine the conditions under which the pERG signal reveals an NMDA receptor component in the retina. We hypothesize that a reduction in D-serine reflects the NMDAR hypofunction found in schizophrenic patients, and that the lack of D-serine impacts the expression of NMDA receptors in the retina such that abnormities can be observed from pERG. The first aim of this study is to pharmacologically reduce and enhance the activity of NMDA receptors with antagonists to evaluate the NMDA component of the pERG. This will be conducted by extracellular recording from isolated perfused retina eye-cups from normal, D-serine deprived, and D-serine elevated mice. The second aim of this study is evaluate the mouse pERG and compare it to the human schizophrenic and normal controls pERG responses. The proposed study directly tackles the NMDAR hypofunction hypothesis for schizophrenia. It embarks in a new way to look at schizophrenia by using signals from the eye that can demonstrate NMDA signaling deficiency hypothesized to account for schizophrenia. Furthermore, these studies in D-serine function will contribute to the current knowledge of the etiology of the disease; which fits directly with the NIMH strategic plan of prevention and treatment for schizophrenia. The public health impact is in understanding the etiology of the disease and improving the diagnostic tools for schizophrenia by using non-invasive signals from the eye, the pERG.

描述（由申请人提供）：精神分裂症是一种慢性破坏性疾病，影响 1% 的人口。目前的治疗只能缓解症状，但不能治愈疾病。不幸的是，精神分裂症的确切原因尚不清楚。多年来，对于精神分裂症有多种假说，其中之一来自对分离麻醉剂的临床研究，该麻醉剂模仿了与精神分裂症相关的阴性症状（情绪和行为状态的破坏）、认知障碍和大脑异常。由于这些解离麻醉剂会拮抗称为 NMDA 受体的谷氨酸受体亚类，因此推测与这些药物一样，精神分裂症也是由 NMDA 受体活性低下引起的。有趣的是，一些精神分裂症患者缺乏 D-丝氨酸（NMDA 受体的共同激动剂）。当使用 D-丝氨酸治疗时，精神分裂症症状会得到改善。通过使用视网膜电图 (ERG) 的变体（称为模式 ERG 或 pERG），我们可以测量视网膜神经节细胞中由光引起的 NMDA 介导的活动。该应用旨在了解不同水平的 D-丝氨酸如何决定 pERG 信号揭示视网膜中 NMDA 受体成分的条件。我们假设 D-丝氨酸的减少反映了精神分裂症患者中发现的 NMDAR 功能减退，并且 D-丝氨酸的缺乏会影响视网膜中 NMDA 受体的表达，从而可以从 pERG 观察到异常。本研究的首要目的是通过拮抗剂从药理学上降低和增强 NMDA 受体的活性，以评估 pERG 的 NMDA 成分。这将通过从正常小鼠、D-丝氨酸缺失小鼠和D-丝氨酸升高小鼠分离的灌注视网膜眼杯进行细胞外记录来进行。本研究的第二个目的是评估小鼠 pERG 并将其与人类精神分裂症患者和正常对照的 pERG 反应进行比较。拟议的研究直接解决了精神分裂症的 NMDAR 功能减退假说。它以一种新的方式来看待精神分裂症，即利用眼睛发出的信号来证明 NMDA 信号传导缺陷，而 NMDA 信号传导缺陷被认为是导致精神分裂症的原因。此外，这些 D-丝氨酸功能研究将有助于加深对该疾病病因学的了解；这直接符合 NIMH 精神分裂症预防和治疗战略计划。对公共卫生的影响在于了解该疾病的病因并通过使用来自眼睛的非侵入性信号 pERG 改进精神分裂症的诊断工具。