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，如精神分裂症和阿尔茨海默病，折磨着数百万美国人。对神经系统疾病相关因素的研究已经发现，几乎所有的广泛性神经系统疾病都存在一个基本的神经元过程--突触可塑性的破坏。突触可塑性，被广泛认为是记忆的细胞基质，描述了特定的修改 神经元连接的反应。因此，改变的机制控制这一过程可能是因果关系的患者患有神经功能障碍的病理生理学。Akt被认为在突触可塑性中起重要作用的一种机制，在精神分裂症、智力残疾和神经退行性疾病中起着越来越重要的作用， 信号通路Akt的三种亚型（Akt1/PKB α、Akt2/PkB β和Akt3/PKB γ）在脑中表达，它们显示出一些重叠的功能，但也已知在包括脑在内的器官中具有不同的生理作用。不同的Akt亚型在突触可塑性过程中所起的作用尚不清楚。这是一个需要克服的重要问题，因为对Akt在突触机制中的功能，特别是不同亚型的作用的更好理解，将允许改进旨在治疗神经系统疾病的诊断和治疗。因此，驱动这一提议的主要假设是Akt亚型被差异地募集用于突触可塑性、认知和记忆形成的神经分子信号传导。本研究的目的是（1）验证Akt亚型对海马长时程增强（LTP）表达的差异调节假说，（2）验证 （3）验证不同Akt亚型在行为和记忆形成中发挥特定作用的假设。为了测试这些目标，我们将使用靶向泛Akt和亚型特异性活性的新型药理学试剂，使我们能够在体内调节Akt功能。为了补充这种方法，我们还将使用Akt突变体从遗传学上探索Akt在突触功能、认知和记忆中的作用。这些结合的方法将被应用于电生理，生物化学和行为分析，以检查神经系统疾病的小鼠模型中的突触可塑性，蛋白质合成和行为表现。我们的方法在概念上和技术上都是创新的，因为我们将利用新的药理学，遗传学和病毒试剂来特异性靶向突触过程和行为中的Akt亚型功能。这项拟议的研究意义重大，因为它解决了有关认知中神经生物学信号分化的基本问题，这对心理健康具有重要意义。通过定义Akt亚型特异性调节突触可塑性和认知，我们的方法将提供新的见解Akt依赖性机制影响神经系统疾病和精神疾病与认知障碍。