Akt regulation of synaptic plasticity and behavior

Akt 调节突触可塑性和行为

• 批准号: 9465132
• 负责人: CHARLES A HOEFFER
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9465132
• 关键词: AKT Signaling Pathway; Address; Affect; Alzheimer' s Disease; American; Automobile Driving; Behavior; Behavioral; Biochemical; Brain; Brain region; Cognition; Complement; Data; Diagnosis; Disease; Disease model; Electrophysiology (science); Excision; Functional disorder; Genetic; Hippocampus (Brain); Human; Impaired cognition; Intellectual functioning disability; Knock-out; Knockout Mice; Knowledge; Lead; Long-Term Depression; Long-Term Potentiation; Mediating; Memory; Mental Health; Mental disorders; Mission; Modeling; Modification; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurologic Dysfunctions; Neurons; Organ; Parahippocampal Gyrus; Patients; Pattern; Performance; Pharmacology; Phase; Physiological; Play; Prevention; Process; Protein Biosynthesis; Protein Isoforms; Proto-Oncogene Proteins c-akt; Public Health; Reagent; Recruitment Activity; Regulation; Research; Rodent Model; Role; Schizophrenia; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Slice; Synapses; Synaptic plasticity; Syndrome; Testing; United States National Institutes of Health; Viral; Work; cognitive enhancement; cognitive function; dentate gyrus; experience; human disease; improved; in vivo; inhibitor/antagonist; innovation; insight; mouse model; mutant; nervous system disorder; novel; public health relevance; response; synaptic function; targeted agent

 DESCRIPTION (provided by applicant): Neurological disorders impacting cognition and memory, such as schizophrenia and Alzheimer's disease, afflict millions of Americans. The search for factors involved in neurological disorders has identified disruptions in a fundamental neuronal process, synaptic plasticity, in nearly all pervasive neurological disorders. Synaptic plasticity, widely held to be the cellular substrate of memory, describes the specific modification of neuronal connections in response to experience. Thus, altered mechanisms controlling this process may be causal in the pathophysiology of patients suffering neurological dysfunction. One mechanism thought to play an important part in synaptic plasticity, with an increasingly important role in schizophrenia, intellectual disability and neurodegenerative diseases, is the Akt signaling pathway. Three isoforms of Akt (Akt1/PKBα, Akt2/PkBβ, and Akt3/PKBγ) are expressed in the brain, and they display some overlapping function but are also known to have distinct physiological roles in organs including the brain. The role played by the different Akt isoforms in synaptic plasticity processes is unknown. This is an important problem to overcome because improved understanding of Akt function in synaptic mechanisms, especially the role of the different isoforms, will allow for improved diagnoses and therapies aimed at treating neurological disorders. Therefore, the main hypothesis driving this proposal is that Akt isoforms are differentially recruited for neuromolecular signaling underlying synaptic plasticity, cognition and memory formation. The aims of this proposal are to (1) test the hypothesis that Akt isoforms differentially regulate the expression of long-term potentiation (LTP) in the hippocampus, (2) test the hypothesis that Akt isoforms differentially regulate the expression of different forms of long-term depression (LTD) in the hippocampus, (3) test the hypothesis that different Akt isoforms play specific roles in behavior and memory formation. To test these aims, we will use novel pharmacological agents that target pan-Akt and isoform-specific activity, enabling us to modulate Akt function in vivo. To complement this approach, we will also genetically probe the role of Akt in synaptic function, cognition, and memory using Akt mutants. These combined approaches will be applied to electrophysiological, biochemical, and behavioral analyses for examining synaptic plasticity, protein synthesis and behavioral performance in mouse models of neurological disorders. Our approach is conceptually and technically innovative because we will utilize novel pharmacological, genetic, and viral reagents to specifically target Akt isoform function in synaptic processes and behavior. This proposed research is significant because it addresses fundamental questions about the differentiation of neurobiological signaling involved in cognition, which has important implications for mental health. By defining Akt isoform-specific regulation of synaptic plasticity and cognition, our approach will provide new insight into Akt-dependent mechanisms affected in neurological diseases and psychiatric disorders associated with cognitive impairments.

 描述（由适用提供）：影响认知和记忆的神经系统疾病，例如精神分裂症和阿尔茨海默氏病，痛苦数百万美国人。在几乎所有普遍的神经系统疾病中，寻找神经系统疾病涉及的因素的搜索已经确定了基本神经元过程中的破坏。突触可塑性被广泛认为是记忆的细胞底物，描述了特定的修饰 响应经验的神经元联系。在患有神经系统功能障碍的患者的病理生理学中，控制这一过程的机制的改变可能是因果关系。一种被认为在突触可塑性中起重要作用的机制，在精神分裂症，智障和神经退行性疾病中起着越来越重要的作用，是AKT 信号通路。 AKT（Akt1/PKBα，Akt2/PKBβ和AKT3/PKBγ）的三种同工型在大脑中表达，它们显示出一些重叠的功能，但也已知在包括大脑在内的器官中具有不同的物理作用。不同的Akt同工型在突触可塑性过程中所起的作用尚不清楚。这是一个重要的问题，因为在突触机制（尤其是不同同工型的作用）中对AKT功能的理解提高了，将允许改善旨在治疗神经系统疾病的诊断和疗法。因此，推动该建议的主要假设是Akt同工型是在突触可塑性，认知和记忆形成下的神经分子信号转导的不同招募的。该提案的目的是（1）检验以下假设：Akt同工型对海马中的长期增强（LTP）的表达不同，（2）测试 Akt同工型对海马中不同形式的长期抑郁（LTD）的表达的表达不同，（3）检验了不同AKT同工型在行为和记忆形成中起特定的作用的假设。为了测试这些目标，我们将使用针对pan-Akt和同工型特异性活性的新型药理学剂，从而使我们能够在体内调节Akt功能。为了完成这种方法，我们还将通常使用AKT突变体探测Akt在突触函数，认知和记忆中的作用。这些组合方法将应用于在神经系统疾病的小鼠模型中检查合成可塑性，蛋白质合成和行为性能的电生理，生化和行为分析。我们的方法在概念和技术上是创新的，因为我们将利用新型的药理，遗传和病毒试剂来专门针对突触过程和行为中的Akt同工型功能。这项拟议的研究很重要，因为它解决了有关认知涉及的神经生物学信号的差异的基本问题，这对心理健康具有重要意义。通过定义对突触可塑性和认知的AKT同工型特异性调节，我们的方法将为与认知障碍相关的神经系统疾病和精神疾病所影响的AKT依赖机制提供新的见解。