Neural function of the human memory-associated protein KIBRA: bridging molecular to circuit-level function

人类记忆相关蛋白 KIBRA 的神经功能：桥接分子与电路水平的功能

• 批准号: 9912847
• 负责人: LENORA J VOLK
• 金额: $ 40.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912847
• 关键词: AMPA Receptors; Acute; Adolescent; Adult; Affect; Animals; Behavior; Behavioral; Binding; Biochemical; Biological; Bipolar Disorder; Brain; Brain Diseases; Brain region; Cognition; Cognition Disorders; Communication; Complex; Custom; Dendritic Spines; Development; Disease; Electrophysiology (science); Financial Hardship; Fluorescence; Functional disorder; Gene Expression; Genetic Polymorphism; Goals; Hippocampus (Brain); Human; Immunoprecipitation; Impairment; Kidney; Knockout Mice; Learning; Long-Term Potentiation; Memory; Memory Disorders; Mental Depression; Mental disorders; Modification; Molecular; Mus; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Neurosciences; Performance; Population; Problem Solving; Process; Proteins; Regulation; Research; Risk Factors; Rodent; Role; Schizophrenia; Slice; Spectrum Analysis; Structure; Synapses; Synaptic plasticity; Tertiary Protein Structure; Testing; Time; Translating; Variant; autism spectrum disorder; behavior influence; cognitive process; density; experimental study; imaging modality; in vivo; information processing; insight; juvenile animal; mature animal; memory retrieval; miniaturize; mutant; neural circuit; novel; protein complex; receptor; recruit; relating to nervous system; resilience; response; scaffold; social; stoichiometry; trafficking; young adult

Understanding the biological basis of complex behavior is a major challenge in neuroscience, and disorders of complex brain function exact an enormous social and financial burden. Solving this problem requires understanding how information processing integrates across molecular, cellular, and circuit levels to influence behavior, and how disease-associated risk factors impact such information processing. Numerous studies demonstrate that common variants of KIBRA (enriched in KIdney and BRAin) associate with human memory performance. KIBRA polymorphisms and gene expression also associate with disorders of complex brain function including schizophrenia (SCZ) and autism spectrum disorder (ASD), and a strikingly large proportion of neuronal KIBRA binding partners associate with SCZ, bipolar disorder, and/or ASD. Thus, KIBRA represents an ideal candidate to reveal molecular mechanisms that control synaptic plasticity and circuit function responsible for normal cognitive processes that are impaired in mental illness. We recently identified KIBRA (enriched in KIdney and BRAin) as a regulator of AMPAR trafficking, synaptic plasticity, and learning and memory in rodents, but the mechanisms by which KIBRA influences these processes and the impact on circuit dynamics remain unclear. This project aims to elucidate KIBRA function across multiple levels of information processing via three aims: 1) identify molecular mechanisms by which KIBRA protein complexes respond to neuronal activity and regulate AMPAR trafficking, 2) determine the molecular and developmental requirements for KIBRA in bidirectional synaptic plasticity, and 3) establish the role of KIBRA in regulating circuit dynamics. Intriguingly, despite robust expression of KIBRA in both the juvenile and adult brain, deficits in synaptic plasticity do not emerge until young adulthood in constitutive KIBRA knockout (KO) mice, a time course consistent with the onset of neurodevelopmental disorders such as SCZ and BPD. Thus, our experiments will also evaluate developmental maturity as a factor impacting the function of KIBRA protein complexes and the neural response to perturbation of KIBRA. To accomplish these goals, we will use domain mutants to identify KIBRA interactors required for trafficking of endogenous AMPARs, employ biochemical and advanced imaging methods (Fluorescence Fluctuation Spectroscopy) to identify activity-regulated dynamics and stoichiometry of KIBRA complexes, examine functional and structural synaptic plasticity in acute brain slices from constitutive and conditional KIBRA KO mice, and perform in vivo electrophysiology in freely behaving mice to evaluate the role of KIBRA in behaviorally-driven circuit dynamics. These proposed studies will reveal critical insight into the function of human-memory- and neurodevelopmental disorder-associated KIBRA complexes at multiple levels of information processing, with broad implications for understanding the mechanisms and neurodevelopmental vulnerabilities underlying complex behavior.

了解复杂行为的生物学基础是神经科学的主要挑战，并且 复杂大脑功能的疾病精确的社会和经济负担。解决这个问题 需要了解信息处理如何跨分子，细胞和电路水平整合到 影响行为，以及与疾病相关的风险因素如何影响此类信息处理。很多的 研究表明，基布拉（富含肾脏和大脑）的常见变体与人相关 内存性能。 Kibra多态性和基因表达也与复杂的疾病相关 包括精神分裂症（SCZ）和自闭症谱系障碍（ASD）的大脑功能以及惊人的大型 神经元KIBRA结合伴侣与SCZ，躁郁症和/或ASD相关的比例。因此， Kibra代表了揭示控制突触可塑性和的分子机制的理想候选者 电路功能负责精神疾病受损的正常认知过程。 我们最近确定Kibra（富含肾脏和大脑）是AMPAR贩运，突触的调节者 啮齿动物中的可塑性以及学习和记忆，但是Kibra影响这些的机制 过程和对电路动力学的影响尚不清楚。该项目旨在阐明Kibra功能 通过三个目标处理多个级别的信息处理：1）确定分子机制 Kibra蛋白复合物对神经元活性做出反应并调节AMPAR运输，2）确定 双向突触可塑性中基布拉的分子和发育要求，3）建立 Kibra在调节电路动力学中的作用。有趣的是，尽管Kibra在这两个方面都强烈地表达 青少年和成人大脑，突触可塑性缺陷直到成年后才会出现 Kibra淘汰（KO）小鼠，这是一种与神经发育障碍的发作一致的时间课程 SCZ和BPD。因此，我们的实验还将评估发展成熟度，这是影响 Kibra蛋白复合物的功能以及对Kibra扰动的神经反应。完成这些 目标，我们将使用域突变体来识别内源性运输所需的kibra互动器 AMPARS，采用生化和高级成像方法（荧光波动光谱） 识别基布拉复合物的活性调节的动力学和化学计量学，检查功能和结构 来自本构和有条件的Kibra KO小鼠的急性脑切片中的突触可塑性，并在体内进行 自由行为小鼠的电生理学评估基布拉在行为驱动的电路动力学中的作用。 这些提出的研究将揭示对人类记忆和神经发育功能的关键见解 在多个级别的信息处理下与障碍相关的Kibra复合物，对 了解复杂行为的基础机制和神经发育脆弱性。