Electrophysiological Endophenotypes of Schizophrenia in Mouse and Man

描述(由申请人提供)：针对中枢神经系统疾病的新药疗法的开发明显落后于其他适应症领域，一些估计表明，美国新化学实体的成功率仅为1%。造成这一问题的因素包括：缺乏与疾病相关的功能筛查，缺乏临床预测的动物模型，以及缺乏可靠和特异的疾病状态生物标志物。这些挑战尤其影响了精神分裂症认知疗法的发现。精神分裂症的认知障碍是这种疾病的核心和衰弱部分，目前还没有有效的治疗方法。开发能够可靠地反映人类认知的动物模型是具有挑战性的，因为动物和人类的认知能力和行为模式从根本上是不同的。弥合这一差距的一种方法是定义在人类疾病状态和相关动物模型中改变的神经活动的特定方面，并将这些措施包括在测试候选药物疗效中。这种方法的强大之处在于，它利用了神经网络水平上的系统发育保守，在物种之间直接翻译。例如，与先前注意到精神分裂症患者皮质网络安装连贯伽马振荡的能力严重障碍的报告一致，我们观察到在钙调神经磷酸酶基因敲除(CNKO)和苯环利定介导的精神分裂症小鼠模型中伽马振荡的变化。我们观察到，在与新奇识别/检测相关的助记任务中，小鼠前额皮质伽马振荡的显著调制在这些小鼠疾病模型中受到损害。在一项旨在确定人类与这种与新奇事物相关的神经活动的等价物的初步研究中，我们在一小群健康志愿者中观察到了在一项新奇古怪的任务中额叶皮质内伽马振荡的类似变化。这些数据支持了神经生理内表型在确定的神经回路中的潜在用途，作为认知疾病状态的客观衡量标准，可以从动物模型转化为人类患者。我们建议识别和验证人类和小鼠的皮质神经生理内表型，这些表型与类似的认知行为任务相关，并受到疾病状态的类似影响。由于人类研究具有与疾病直接相关的优势，因此将采用协调和互惠的方法，而啮齿动物系统可以提供更高分辨率的电生理措施，并可以通过遗传和药理学手段进行操纵，以检验特定的疾病假说。我们认为，在啮齿动物和人类之间保守的疾病状况的电生理内表型将为精神分裂症疾病状态和临床试验中评估候选药物疗效的客观生物标志物提供客观的生物标志物，以及为患者个性化最佳治疗方案提供诊断工具。因此，这项提案中概述的研究将使大量精神分裂症和相关疾病患者受益。 公共卫生相关性：精神分裂症影响全球约1%的人口。这项提案中概述的研究将支持开发创新的方法和技术，以确定治疗精神分裂症认知缺陷的新疗法，这是一项尚未得到满足的主要医疗需求。这项研究将对大量精神分裂症患者、他们的家人和照顾者产生积极影响。特别是，改善精神分裂症患者的认知结果将有助于患者提高生活质量，使他们能够在个人和职业生活中更有效地发挥作用。

DESCRIPTION (provided by applicant): Development of new drug therapies for CNS disorders has significantly lagged behind other indication areas, with some estimates suggesting only a 1% success rate for new chemical entities in the United States. Factors contributing to this problem include: lack of disease-relevant functional screens, lack of clinically predictive animal models and absence of reliable and specific biomarkers of disease state. These challenges have particularly impacted the discovery of cognitive therapies for schizophrenia. The cognitive impairments in schizophrenia comprise a core and debilitating component of the illness for which there are currently no effective therapies. Development of animal models that can reliably mirror human cognition is challenging, since the cognitive capacities and behavioral repertoires of animals and humans are fundamentally distinct. One approach to bridging this gap is to define specific aspects of neural activity that are altered in the human disease state and in cognate animal models, and to include such measures in testing candidate drug efficacy. The power of this approach is that it takes advantage of phylogenetic conservation at the level of neural networks to translate directly between species. For example, in accord with previous reports noting a severe dysfunction in the ability of cortical networks to mount coherent gamma oscillations in schizophrenia patients, we have observed alterations in gamma oscillations in the calcineurin knockout (CNKO) and phencyclidine- mediated mouse models of schizophrenia. We observed significant modulation of gamma oscillations in the prefrontal cortex of mice during mnemonic tasks associated with novelty recognition/detection that is impaired in these mouse disease models. In an initial study aimed at identifying human equivalencies of this novelty- related neural activity, we have observed similar changes in gamma oscillations within frontal cortex during a novelty oddball task in a small population of healthy volunteers. These data provide support for the potential utility of neurophysiological endophenotypes within defined neural circuits as objective measures of cognitive disease states that can be translated from animal models to human patients. We propose to identify and validate cortical neurophysiological endophenotypes in both humans and mice that are associated with analogous cognitive behavioral tasks and similarly affected by disease state. A coordinated and reciprocal approach will be applied since human studies have the advantage of direct disease relevance, while rodent systems can provide higher resolution electrophysiological measures and can be manipulated via genetic and pharmacological means to test specific disease hypotheses. We propose that identified electrophysiological endophenotypes of the disease condition that are conserved between rodents and man will provide objective biomarkers for schizophrenia disease state and for assessing drug candidate efficacy during clinical trials, as well as diagnostic tools for personalization of optimal treatment regimes for patients. The research outlined in this proposal thus stands to benefit the large population of patients with schizophrenia and related illnesses. PUBLIC HEALTH RELEVANCE: Schizophrenia affects approximately 1% of the population worldwide. The research outlined in this proposal will support the development of innovative approaches and technologies to identify new therapies for the cognitive deficits in schizophrenia, which are a major unmet medical need. This research will have a positive impact on a significant population of schizophrenia patients, their family members and caregivers. In particular, improving the cognitive outcome in schizophrenia will help patients to improve their quality of life, enabling them to function more effectively in their personal and professional lives.