Mitochondrial AKAP1 signaling in chronic stress-induced prefrontal structural & functional plasticity

慢性应激诱导的前额叶结构中的线粒体 AKAP1 信号传导

基本信息

批准号：
9789933
负责人：
JASON J RADLEY
金额：
$ 19.06万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-25 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789933
关键词：
A kinase anchoring protein Accounting Address Adrenal Glands Adverse effects Animal Model Animals Applications Grants Behavioral Binding Binding Proteins Biochemical Genetics Cell Nucleus Cell Respiration Cells Chronic Chronic stress Cyclic AMP-Dependent Protein Kinases Data Data Set Dendritic Spines Development Dyes Dynamin Electrons Exposure to Foundations Functional disorder Future Glucocorticoids Goals Human Image Analysis Immunoblot Analysis Impaired cognition Impairment Injections Intervention Knockout Mice Laboratories Link Major Depressive Disorder Medial Mediating Membrane Potentials Mental disorders Messenger RNA Microscopic Microscopy Mitochondria Mitochondrial Proteins Movement Mus Neurodegenerative Disorders Neuronal Plasticity Neurons Outer Mitochondrial Membrane Oxidative Phosphorylation Pathogenesis Pathway interactions Phosphorylation Pituitary Gland Play Prefrontal Cortex Protein Dephosphorylation Protein phosphatase Proteins Research Resolution Role Scaffolding Protein Shapes Signal Transduction Signaling Molecule Stress Structure Subfamily lentivirinae Synapses Synaptic Transmission Therapeutic Intervention Three-Dimensional Imaging Time Tissues Work base behavioral plasticity calcineurin phosphatase cognitive function delta opioid receptor depressive symptoms experimental study follow-up functional plasticity hippocampal pyramidal neuron insight mitochondrial membrane morphometry mutant novel overexpression reconstitution recruit stressor targeted treatment

项目摘要

Project Summary Optimal functioning of the medial prefrontal cortex (mPFC) relies on synaptic connections made onto dendritic spines in pyramidal neurons. Prefrontal dysfunction resulting from chronic stress and stress-related psychiatric illnesses are each linked to decreases in dendritic spine number and shape alterations in this cortical region. Work from our laboratory and others has shown that chronic stress and elevated glucocorticoids, the end products of the hypothalamo-pituitary-adrenal stress axis activation, induce structural deficits marked by dendritic spine loss in mPFC and impaired prefrontal cognitive functions. While some progress has been made in elucidating the biochemical and genetic components underlying disrupted prefrontal plasticity in animal models of psychiatric illnesses, more work is needed to identify the cellular mechanisms accounting for these changes to help develop targets for therapeutic intervention. In this regard, recent consideration has been given to the idea that mitochondrial deficiencies may contribute to chronic stress-induced cognitive impairments and the pathogenesis of human psychiatric disorders. A-kinase anchoring protein 1 (AKAP1) is a mitochondrial scaffolding protein that recruits protein kinase A (PKA) to the outer mitochondrial membrane leading to phosphorylation and inactivation of the mitochondrial fission protein, dynamin-related protein 1 (Drp1). We have previously shown that AKAP1 increases mitochondrial membrane potential, an indicator of the cell's ability to generate ATP by oxidative phosphorylation, whereas deletion of AKAP1 leads to mitochondrial fission and dendritic spine loss in cortical neurons. These observations have culminated in the novel hypothesis that chronic stress-induced alterations in prefrontal structural and functional plasticity are mediated by diminished AKAP1 signaling in mPFC neurons. Therefore, the goal of this exploratory/developmental R21 is to examine the role of AKAP1 in chronic stress-induced dendritic spine loss and functional compromise in mPFC neurons, thus developing a data set for a future R01. In aim 1, we will interrogate whether CVS's adverse effects on prefrontal dendritic spine structure are accompanied by AKAP1 loss, Drp1 dephosphorylation/activation, and mitochondrial fragmentation. Aim 2 will use AKAP1 KO mice and lentiviral delivery of wild type and PKA-binding deficient AKAP1 to identify the signaling mechanisms accounting for disruption of prefrontal mitochondrial, dendritic spine, and behavioral alterations. The long-term goal of this line of research is to elucidate the key mechanisms linking mitochondrial dynamics to stress-related prefrontal dysfunction, as this is a common underlying feature of stress-related psychiatric disorders such as major depressive illness.

项目概要内侧前额皮质 (mPFC) 的最佳功能依赖于树突上的突触连接锥体神经元中的棘。慢性压力和与压力相关的精神疾病导致的前额叶功能障碍每种疾病都与该皮质区域树突棘数量的减少和形状的改变有关。我们实验室和其他实验室的工作表明，慢性压力和糖皮质激素升高，最终下丘脑-垂体-肾上腺应激轴激活的产物，引起结构缺陷，其特征为 mPFC 中的树突棘缺失和前额认知功能受损。虽然已经取得了一些进展阐明动物前额叶可塑性破坏背后的生化和遗传成分精神疾病模型，需要更多的工作来确定解释这些疾病的细胞机制改变以帮助制定治疗干预的目标。对此，近期考虑鉴于线粒体缺陷可能导致慢性压力诱发的认知能力人类精神疾病的损伤和发病机制。 A-激酶锚定蛋白 1 (AKAP1) 是一种线粒体支架蛋白，将蛋白激酶 A (PKA) 招募到线粒体外膜导致线粒体裂变蛋白、动力相关蛋白 1 的磷酸化和失活（Drp1）。我们之前已经证明 AKAP1 会增加线粒体膜电位，这是线粒体膜电位的一个指标细胞通过氧化磷酸化产生 ATP 的能力，而 AKAP1 的缺失会导致皮质神经元的线粒体裂变和树突棘损失。这些观察最终导致新的假设是慢性压力引起的前额叶结构和功能的改变可塑性是由 mPFC 神经元中 AKAP1 信号减弱介导的。因此，本次活动的目标探索性/发育性 R21 旨在检查 AKAP1 在慢性应激引起的树突棘损失中的作用以及 mPFC 神经元的功能受损，从而为未来的 R01 开发数据集。在目标 1 中，我们将询问 CVS 对前额叶树突棘结构的不利影响是否伴随着 AKAP1 丢失、Drp1 去磷酸化/激活和线粒体断裂。目标 2 将使用 AKAP1 KO 小鼠慢病毒递送野生型和 PKA 结合缺陷的 AKAP1 以鉴定信号传导机制解释前额叶线粒体、树突棘的破坏和行为改变。长期来看这一系列研究的目标是阐明线粒体动力学与应激相关的关键机制前额叶功能障碍，因为这是与压力相关的精神疾病的常见潜在特征，例如严重抑郁症。