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.

项目摘要内侧前额叶皮层（MPFC）的最佳功能依赖于在树突状的突触连接金字塔神经元中的刺。慢性应激和与压力有关的精神病产生的前额叶功能障碍疾病各自与该皮质区域的树突状脊柱数量和形状改变有关。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，结束下丘脑 - 垂体 - 肾上腺应激轴激活的产物，诱导结构缺陷 MPFC中的树突状脊柱丧失和前额叶认知功能受损。虽然取得了一些进展在阐明动物中破坏前额叶可塑性的生化和遗传成分时精神病的模型，需要更多的工作来确定有关这些元件的细胞机制更改以帮助开发治疗干预的目标。在这方面，最近的考虑是给出这样的想法，即线粒体缺陷可能有助于慢性应激引起的认知能力障碍和人类精神疾病的发病机理。 A-激酶锚定蛋白1（AKAP1）是线粒体脚手架蛋白，将蛋白激酶A（PKA）募集到外部线粒体膜导致线粒体裂变蛋白的磷酸化和灭活，Dynamin相关蛋白1 （DRP1）。我们以前已经表明，AKAP1增加了线粒体膜电位，这是细胞通过氧化磷酸化产生ATP的能力，而AKAP1的缺失导致皮质神经元中的线粒体裂变和树突状脊柱丧失。这些观察结果达到了慢性应激诱导的前额叶结构和功能改变的新假设可塑性是由MPFC神经元中AKAP1信号降低的介导的。因此，目标的目标探索性/发育R21是检查AKAP1在慢性应激引起的树突状脊柱丧失中的作用并在MPFC神经元中妥协，从而为未来R01开发了数据集。在AIM 1中，我们将询问CVS是否对前额叶树突状脊柱结构的不良影响伴随着AKAP1 损失，DRP1去磷酸化/激活和线粒体碎片。 AIM 2将使用AKAP1 KO小鼠和野生型和PKA结合缺乏AKAP1的慢病毒输送以识别信号传导机制考虑到前额叶线粒体，树突状脊柱和行为改变的破坏。长期这一研究的目标是阐明将线粒体动力与压力相关的关键机制前额外的功能障碍，因为这是与压力有关的精神疾病的共同基础特征，例如重度抑郁症。