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，在美国，新化学实体的成功率只有1%。造成这一问题的因素包括：缺乏与疾病相关的功能筛选，缺乏临床预测动物模型，缺乏可靠和特定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构成了该疾病的核心和衰弱成分，目前尚无有效的治疗方法。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特征从根本上是不同的。弥合这一差距的一种方法是确定在人类疾病状态和同源动物模型中被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功效中。这种方法的强大之处在于，它利用了神经网络层面的系统发育守恒，直接在物种之间进行翻译。例如，与先前的报道一致，在精神分裂症患者中，皮质网络建立连贯伽马振荡的能力存在严重功能障碍，我们在钙调磷酸酶敲除（CNKO）和苯环利定介导的精神分裂症小鼠模型中观察到伽马振荡的改变。我们观察到，在这些小鼠疾病模型中受损的与新奇识别/检测相关的记忆任务期间，小鼠前额叶皮层的伽马振荡显著调节。在一项旨在确定人类与这种新奇相关的神经活动等效性的初步研究中，我们在一小群健康志愿者中观察到，在新奇古怪的任务中，额叶皮层内的伽马振荡发生了类似的变化。这些数据支持了神经生理内表型作为认知疾病状态客观测量的潜在效用，可以从动物模型转化为人类患者。我们建议在人类和小鼠中识别和验证与类似认知行为任务相关的皮层神经生理内表型，并同样受到疾病状态的影响。由于人类研究具有直接疾病相关性的优势，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测量，并且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。我们提出，在啮齿动物和人类之间保守的疾病状态的确定的电生理内表型将为精神分裂症疾病状态提供客观的生物标志物，并在临床试验中评估候选药物的疗效，以及为患者提供个性化最佳治疗方案的诊断工具。因此，本提案中概述的研究将使大量患有精神分裂症和相关疾病的患者受益。

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.