Calcium Signaling & Prefrontal Deficits in Schizophrenia

在目前的CCNMD中，我们建议进行一项新的翻译研究计划，涉及精神分裂症和相关疾病中导致背外侧前额叶皮质(DLPFC)认知功能障碍的内源性过程。该提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患者细胞内钙相关级联反应的缺陷，其中包括最近发现的一类新的影响钙的多巴胺(DA)受体相互作用蛋白(DIPs) 模型系统中的信令。我们认为，这些缺陷可能由许多原因引起，构成了疾病的潜在原因机制，可以解释不同和广泛的神经病理以及高阶功能的显著脆弱性。在精神分裂症DA假说的启发下，广泛的研究尚未在DA系统的任何特定组成部分中分离出明显的疾病相关异常，但多巴胺在精神疾病核心认知功能障碍中的作用是不可否认的。目前的CCNMD由4所不同大学的项目组成，旨在将多巴胺药理学、细胞生物学、电路机制和神经过程与 动物和病人的行为终点。最先进的方法包括分离新的滴液并在细胞培养中表征其细胞功能，以及基于广泛的临床前研究对精神分裂症患者进行的临床试验。一个子项目使用分子、神经化学和解剖学工具询问患者和对照组死后大脑中的水滴状况。另一个子项目检查了大脑皮质脑片中已识别的神经元和回路中的DA调制和DA介导的神经相互作用的钙信号。对啮齿动物中的PKA和PKC信号进行了研究，包括表达水滴蛋白的基因工程小鼠。其他项目将询问在正常和慢性药物疗法下执行认知任务的非人类灵长类动物的类似药理和生理机制，旨在阐明认知功能的基本特性，并同时与项目9中的临床研究平行。这些基于新概念和发现的多维项目具有挑战性和冒险精神，但所有PL都有有效互动和富有成效的合作的长期记录，以证明投资于该提案的潜力是合理的。

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.