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NMDA receptor dysfunction and development of translational biomarkers for autism and schizophrenia.

机译：NMDA受体功能障碍和自闭症和精神分裂症的翻译生物标志物的发展。

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摘要

Autism and schizophrenia are neurodevelopmental disorders which both have highly disabling negative and cognitive symptoms with few effective treatments. A challenge to developing effective therapeutics is a dearth of pre-clinical models. Part of the difficulty in developing predictive models is that the symptoms being treated are complex, and difficult to reduce to a simple behavioral task. Therefore, the use of endophenotypes from methods such as EEG presents a new promising avenue for a model of complex human behaviors pre-clinically. New evidence suggests that autism and schizophrenia have reliable electrophysiological endophenotypes, some of which have been correlated to negative and cognitive symptoms. These endophenotypes therefore represent a possible new pathway for understanding the disrupted circuits in both diseases and developing treatments.;Evidence has been accumulating for glutamate disruption in both schizophrenia and autism; accordingly, pre-clinical models are being developed around NMDA receptor (NMDAR) disruption to examine both diseases. NMDA disruption models have been used for many behavioral tasks, but only a few possible electrophysiological endophenotypes such as ERP amplitudes have been investigated. Investigating pre-clinical models of established clinical endophenotypes could lead to better translational biomarkers of disease symptoms.;This thesis's unifying theme is the study of how glutamate disruption can recreate the electrophysiological endophenotypes present in autism and schizophrenia and develop their use as translational biomarkers in both diseases. The primary models of focus are acute NMDA antagonist administration and NMDAR knockdown of PV interneurons. I used these models to examine the relationship between dose and EEG changes, along with the perturbations present with NMDAR disruption in PV interneurons. I investigated the degree to which NMDAR antagonists recreate signal-to-noise ratio (SNR) and timing perturbations in schizophrenia, and found a dose-dependent decrease in SNR and timing consistency. I assessed the extent to which low dose NMDAR antagonism recreates latency and gamma synchrony perturbations present in autism and found latency was increased and gamma synchrony was decreased dose-dependently. I examined the extent to which Parvalbumin (PV) containing interneurons cell type selective NR1 KO mice recreate the clinical EEG profiles of autism and found selective deficits in social behavior and increases in N1 latency.
机译：自闭症和精神分裂症是神经发育障碍，它们都具有高度致残的负面和认知症状，几乎没有有效的治疗方法。开发有效疗法的挑战是缺乏临床前模型。开发预测模型的困难之一是要治疗的症状很复杂，很难减少为简单的行为任务。因此，使用来自诸如EEG之类的方法的内表型为临床前复杂的人类行为模型提供了一条新的有希望的途径。新证据表明，自闭症和精神分裂症具有可靠的电生理内表型，其中一些已与阴性和认知症状相关。因此，这些内表型代表了一种可能的新途径，可用于理解疾病和正在发展的治疗方法中的破坏性回路。精神分裂症和自闭症中谷氨酸破坏的证据不断积累。因此，正在围绕NMDA受体（NMDAR）破坏建立临床前模型，以检查两种疾病。 NMDA破坏模型已用于许多行为任务，但仅研究了几种可能的电生理内表型，例如ERP振幅。研究临床内表型的临床前模型可能会导致更好的疾病症状翻译生物标志物。；本论文的统一主题是研究谷氨酸破坏如何重现自闭症和精神分裂症中存在的电生理内表型并发展其在这两种形式中的翻译生物标志物的用途疾病。焦点的主要模型是急性NMDA拮抗剂给药和PV中间神经元的NMDAR敲低。我使用这些模型来检查剂量和脑电图变化之间的关系，以及PV中间神经元中NMDAR破坏引起的扰动。我研究了NMDAR拮抗剂在精神分裂症中重建信噪比（SNR）和时序扰动的程度，并发现SNR和时序一致性的剂量依赖性降低。我评估了低剂量NMDAR拮抗作用在一定程度上重现了孤独症中的潜伏期和伽马同步扰动，发现潜伏期增加了，而伽马同步减少了剂量依赖性。我检查了含有小白蛋白（PV）的中性神经元细胞类型选择性NR1 KO小鼠在多大程度上重现了自闭症的临床EEG谱，发现社交行为的选择性缺陷和N1潜伏期的增加。

著录项

  • 作者

    Saunders, John Anson, IV.;

  • 作者单位

    University of Pennsylvania.;

  • 授予单位 University of Pennsylvania.;
  • 学科 Biology Neuroscience.;Engineering Biomedical.;Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 100 p.
  • 总页数 100
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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