Electrophysiological Endophenotypes of Schizophrenia in Mouse and Man

描述（由申请人提供）：CNS疾病新药治疗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：缺乏疾病相关的功能筛选，缺乏临床预测动物模型，缺乏可靠和特异性的疾病状态生物标志物。这些挑战特别影响了精神分裂症认知疗法的发现。精神分裂症中的认知障碍包括疾病的核心和使人衰弱的组成部分，目前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具有挑战性，因为动物和人类的认知能力和行为库从根本上是不同的。弥合这一差距的一种方法是定义在人类疾病状态和同源动物模型中改变的神经活动的特定方面，并在测试候选药物功效时包括这些措施。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性，直接在物种之间进行翻译。例如，与注意到精神分裂症患者中皮质网络建立相干γ振荡能力的严重功能障碍的先前报道雅阁，我们已经观察到钙调磷酸酶敲除（CNKO）和苯环利定介导的精神分裂症小鼠模型中γ振荡的改变.我们观察到显着的调制γ振荡在前额叶皮层的小鼠在记忆任务与新奇的识别/检测，在这些小鼠疾病模型受损。在一项旨在确定这种新奇相关神经活动的人类等效性的初步研究中，我们在一小部分健康志愿者中观察到了一项新奇古怪任务期间额叶皮层内伽马振荡的类似变化。这些数据提供了支持的潜在效用的神经生理学内表型内定义的神经回路作为认知疾病状态的客观措施，可以从动物模型翻译到人类患者。我们建议识别和验证人类和小鼠的皮质神经生理学内表型，这些内表型与类似的认知行为任务相关，并且同样受到疾病状态的影响。将采用协调和互惠的方法，因为人类研究具有直接疾病相关性的优势，而啮齿动物系统可以提供更高分辨率的电生理测量，并可以通过遗传和药理学手段进行操作，以测试特定的疾病假设。我们建议，确定的电生理内表型的疾病状况之间的啮齿动物和人的保守性将提供客观的生物标志物的精神分裂症疾病状态和评估候选药物的疗效在临床试验中，以及诊断工具的个性化的最佳治疗方案的患者。因此，本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。

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.