Akt regulation of synaptic plasticity and behavior

 描述(申请人提供)：影响认知和记忆的神经疾病，如精神分裂症和阿尔茨海默病，困扰着数百万美国人。对神经疾病相关因素的研究发现，在几乎所有弥漫性神经疾病中，基本神经过程--突触可塑性--的中断。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 神经元连接对经验的反应。因此，控制这一过程的机制改变可能是神经功能障碍患者的病理生理学的原因。一种被认为在突触可塑性中发挥重要作用的机制是Akt，它在精神分裂症、智能障碍和神经退行性疾病中发挥着越来越重要的作用。 信号通路。Akt的三种亚型(Akt1/PKBα、AkT2/PKBβ和Akt3/PKBγ)在脑中表达，它们具有重叠的功能，但在包括大脑在内的器官中也有不同的生理作用。不同Akt亚型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，因为提高对Akt在突触机制中的功能，特别是不同亚型的作用的了解，将有助于改进旨在治疗神经疾病的诊断和治疗。因此，支持这一假设的主要假设是Akt亚型被差异地招募用于突触可塑性、认知和记忆形成的神经分子信号转导。这个建议的目的是(1)检验Akt亚型不同地调节海马区长时程增强(LTP)表达的假说，(2)检验 Akt亚型差异调节不同形式的长期抑郁(LTD)在海马区表达的假说，(3)检验不同Akt亚型在行为和记忆形成中发挥特定作用的假说。为了测试这些目标，我们将使用针对PAN-Akt和异构体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。为了补充这一方法，我们还将使用Akt突变体从遗传学角度探讨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、生化和行为分析，以检查神经疾病小鼠模型的突触可塑性、蛋白质合成和行为表现。我们的方法在概念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专门针对突触过程和行为中的Akt亚型功能。这项拟议的研究具有重要意义，因为它解决了与认知有关的神经生物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异构体对突触可塑性和认知的特定调节，我们的方法将为研究与认知障碍相关的神经疾病和精神障碍中影响Akt依赖的机制提供新的见解。

 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.