Akt regulation of synaptic plasticity and behavior

Akt 调节突触可塑性和行为

• 批准号: 9037720
• 负责人: CHARLES A HOEFFER
• 金额: $ 33.24万
• 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/9037720
• 关键词: Address; Affect; Alzheimer' s Disease; American; Automobile Driving; Behavior; Behavioral; Biochemical; Brain; Brain region; Cognition; Complement; Data; Diagnosis; Disease; Electrophysiology (science); Excision; Functional disorder; Genetic; Health; 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; 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; Work; cognitive function; dentate gyrus; experience; human disease; improved; in vivo; inhibitor/antagonist; innovation; insight; mouse model; mutant; nervous system disorder; novel; response; synaptic function; targeted agent; virus genetics

 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（由申请人提供）：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病，困扰着数百万美国人。对神经系统疾病相关因素的研究已经发现，几乎所有疾病都存在基本神经过程（突触可塑性）的破坏。神经系统疾病，被广泛认为是记忆的细胞基础，描述了特定的修饰。 因此，控制这一过程的机制改变可能是神经功能障碍患者病理生理学的原因，这种机制被认为在突触可塑性中发挥着重要作用，在精神分裂症、智力障碍和精神障碍中发挥着越来越重要的作用。神经退行性疾病，是 Akt Akt 的三种亚型（Akt1/PKBα、Akt2/PkBβ 和 Akt3/PKBγ）在大脑中表达，它们表现出一些重叠的功能，但也已知在包括大脑在内的器官中具有不同的生理作用。不同 Akt 异构体在突触可塑性过程中的作用尚不清楚，这是一个需要克服的重要问题，因为我们可以更好地了解 Akt 功能在突触机制中的作用，尤其是不同异构体的作用。因此，推动该提议的主要假设是，Akt 亚型在突触可塑性、认知和记忆形成的神经分子信号传导中存在差异。该提议的目的是（ 1) 检验 Akt 同工型差异调节海马长时程增强 (LTP) 表达的假设，(2) 检验 Akt 同工型差异调节海马中不同形式的长期抑郁 (LTD) 表达的假设，(3) 检验不同 Akt 同工型在行为和记忆形成中发挥特定作用的假设。使用针对泛 Akt 和亚型特异性活性的新型药物制剂，使我们能够在体内调节 Akt 功能。为了补充这一方法，我们还将从基因角度探讨 Akt 在突触功能中的作用。这些组合方法将应用于电生理学、生化和行为分析，以检查神经系统疾病小鼠模型的突触可塑性、蛋白质合成和行为表现，因为我们将利用这种方法在概念上和技术上都是创新的。新颖的药理学、遗传和病毒试剂专门针对突触过程和行为中的 Akt 同工型功能。这项拟议的研究意义重大，因为它解决了认知中涉及的神经生物学信号分化的基本问题，这对心理具有重要意义。通过定义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 依赖性机制提供新的见解。