Novel Signal Transduction Mechanisms in Learning and Memory

描述(由申请人提供)：认知依赖于神经回路的正确形成以及这些回路对经验的适应。陈述性学习和记忆背后的细胞和分子机制构成了基础神经生物学研究的一个主要领域，具有相当大的临床意义。认知生化机制的失调可能导致神经发育和神经退行性疾病，包括自闭症、阿尔茨海默氏症、智力低下、精神分裂症以及注意力缺陷和多动障碍。我们重点研究了涉及神经元蛋白激酶CDK5的突触信号转导机制，目的是确定它在学习和记忆中的作用。我们开发了一种创新的转基因方法，可以在成年小鼠的整个大脑中诱导神经元蛋白的敲除。这导致了神经元蛋白激酶CDK5控制突触可塑性、学习和记忆的发现。我们发现这是由于NMDA受体NR2B亚单位的水平和表面表达的变化。在这里，我们建议描述CDK5和NR2B之间的相互作用，评估CDK5-NR2B相互作用在突触可塑性中的作用，并评估CDK5-NR2B相互作用在学习和记忆中的作用。拟议的研究是基于我们的初步发现，CDK5在一个新的位置磷酸化NR2B，这种磷酸化控制着受体到突触细胞表面的移位。我们将描述这一重要位点对磷酸化/去磷酸化的调控，并确定其生理功能。我们假设，NR2B的磷酸化状态在学习过程中受到动态调节，对于巩固海马体的记忆是必不可少的。此外，我们发现正在开发基于干扰CDK5-NR2B体外和体内相互作用的小的类药物干扰肽。我们将使用这种选择性靶向的方法来操纵CDK5-NR2B的相互作用，并双向控制NR2B的磷酸化状态和表面水平。这将使我们能够调节海马体中的突触可塑性、学习和记忆。因此，通过结合先进的转基因、生化、神经生理学和行为学方法，我们将定义一种重要的新的认知调节机制，并将其作为可能开发创新的干扰策略来治疗认知障碍的目标。 公共卫生相关性：与许多其他疾病不同，神经发育和神经退行性疾病的高发病率和医疗负担并没有因现代医学的进步而减少。许多神经精神和神经疾病，如自闭症、阿尔茨海默氏症、智力低下、精神分裂症、注意力缺陷和多动障碍，可能涉及调节认知的细胞和分子机制的失调。这项研究的目标是识别和了解新的生化机制，这些机制调节认知和开发试剂，改善学习和记忆，并导致精神疾病和神经障碍的创新破坏策略。

DESCRIPTION (provided by applicant): Cognition is dependent upon the proper formation of neural circuits and the adaptations of those circuits in response to experience. The cellular and molecular mechanisms underlying declarative learning and memory constitute a predominant area in basic neurobiological research and are of considerable clinical relevance. Dysregulation of the biochemical mechanisms underlying cognition likely contributes to neurodevelopmental and neurodegenerative disorders including autism, Alzheimer's, mental retardation, schizophrenia, and attention deficit and hyperactivity disorder. We have focused on synaptic signal transduction mechanisms involving the neuronal protein kinase Cdk5, with the goal of determining its role in learning and memory. We developed an innovative transgenic approach that allowed the induction of knockout of the neuronal protein throughout the brain of adult mice. This led to the discovery that the neuronal protein kinase Cdk5 governs synaptic plasticity, learning, and memory. We found that this was due to changes in the levels and surface expression of the NR2B subunit of the NMDA receptor. Here we propose to characterize the interactions between Cdk5 and NR2B, evaluate the role of Cdk5-NR2B interactions in synaptic plasticity, and assess the role of Cdk5-NR2B interaction in learning, and memory. The proposed studies are based on our preliminary findings that Cdk5 phosphorylates NR2B at a novel site and this phosphorylation controls the translocation of the receptor to the synaptic cell surface. We will characterize the regulation of this important site with regard to phosphorylation/dephosphorylation and define its physiological function. We hypothesize that the phosphorylation state of NR2B is dynamically regulated during learning and essential for consolidation of memory in the hippocampus. Furthermore, we show that are developing small drug-like interfering peptides based that disrupt Cdk5-NR2B interactions in vitro and in vivo. We will use this selective targeting approach to manipulate Cdk5-NR2B interactions and bidirectionally control the phosphorylation state and surface levels of NR2B. This will allow us to modulate synaptic plasticity, learning and memory in the hippocampus. Thus by combining advanced transgenic, biochemical, neurophysiological and behavioral approaches, we will define an important new mechanism that mediates cognition and demonstrate it as a target for the possible development of innovate disruption strategies to treat cognitive disorders. PUBLIC HEALTH RELEVANCE: Unlike many other diseases, the high levels of morbidity and health care burden of neurodevelopmental and neurodegenerative disorders has not been reduced by modern advances in medicine. Many neuropsychiatric and neurological illnesses such as autism, Alzheimer's, mental retardation, schizophrenia, and attention deficit and hyperactivity disorder may involve the dysregulation of the cellular and molecular mechanisms that mediate cognition. The goal of this research is to identify and understand novel biochemical mechanisms that mediate cognition and develop reagents that will improve learning and memory, and lead to innovative disruption strategies for mental illness and neurological disorders.