Calcium Signaling & Prefrontal Deficits in Schizophrenia

在本CCNMD，我们建议进行一个新的程序的翻译研究有关的内源性过程负责认知功能障碍的背外侧前额叶皮层（DLPFC）在精神分裂症和相关疾病。该建议的中心假设是基于一组新的发现，这些发现指出精神分裂症中Ca2相关细胞内级联的缺陷，其中包括最近发现的一类新的多巴胺（DA）受体相互作用蛋白（DRIP），其影响钙离子 模型系统中的信号。我们认为，这些缺陷，这可能是由许多原因引起的，构成了潜在的因果机制的障碍，可以解释多样和广泛的神经病理学以及突出的脆弱性，高阶功能。受精神分裂症DA假说启发的广泛研究尚未在DA系统的任何特定组成部分中分离出明确的疾病相关异常，但多巴胺在精神疾病核心认知功能障碍中的作用不容否认。目前的CCNMD由4所不同大学的项目组成，旨在整合多巴胺药理学，细胞生物学，电路机制和神经元过程， 动物和患者的行为终点。最先进的方法包括分离新型DRIP和在细胞培养物中表征其细胞功能，以及基于广泛的临床前研究在精神分裂症患者中进行临床试验。其中一个子项目用分子、神经化学和解剖学工具研究了DRIP在患者和对照组死后大脑中的状态。另一个子项目研究DA调制和DA介导的钙信号的神经相互作用，在确定的神经元和电路在PFC皮层切片。在啮齿类动物，包括基因工程小鼠表达DRIPs的PKA和PKC信号的研究，进行。其他项目将在非人灵长类动物中探究相似的药理学和生理学机制，这些灵长类动物在正常和慢性药物方案下执行认知任务，旨在阐明认知功能的基本特性，同时与项目9中的临床研究平行。这些基于新概念和新发现的多维项目具有挑战性和风险性，但所有PI都有长期的有效互动和富有成效的合作记录，以证明对该提案潜力的投资是合理的。

In the present CCNMD we propose to conduct a new program of translational research concerned with the endogenous processes responsible for cognitive dysfunctions of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia and related disorders. The central hypothesis of the proposal is based on a new set of findings pointing to deficiencies in Ca2-associated intracellular cascades in schizophrenia, among them the recent discovery of a new class of dopamine (DA) receptor interacting proteins (DRIPs) which affect calcium signaling in model systems. We propose that such deficiencies, which may arise from many causes, constitute the underlying causal mechanism in the disorder and can account for both diverse and widespread neuropathologies as well as prominent vulnerability of higher-order functions. Extensive research inspired by the DA hypothesis of schizophrenia has yet to isolate a clear disease-associated abnormality in any particular component of the DA system, but the role of dopamine in the core cognitive dysfunctions of mental diseases cannot be denied. The present CCNMD is comprised of projects at 4 different universities designed to integrate dopamine pharmacology, cell biology, circuit mechanisms and neuronal processes with behavioral endpoints in animals and patients. State-of-the-art methodologies range from the isolation of novel DRIPs and characterization of their cellular functions in cell cultures through a clinical trial in schizophrenia patients based on a broad array of preclinical research. One subproject interrogates the status of DRIPs in postmortem brains from patients and controls with molecular, neurochemical and anatomical tools. Another subproject examines DA modulation and DA mediated calcium signaling of neural interactions in identified neurons and circuits in PFC cortical slices. Studies of PKA and PKC signaling in rodents, including mice genetically engineered to express DRIPs, are carried out. Other projects will interrogate similar pharmacological as well as physiological mechanisms in nonhuman primates performing cognitive tasks under normal and chronic drug regimens designed to elucidate basic properties of cognitive function and simultaneously parallel the clinical study in Project 9. These multidimensional projects based on novel concepts and discoveries are challenging and risk-taking, but all Pl's have a long record of effective interactions and productive collaboration to justify investment in the potential of this proposal.