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

项目摘要 内侧前额叶皮层（mPFC）的最佳功能依赖于树突状细胞上的突触连接。 锥体神经元中的棘。慢性应激和应激相关精神障碍导致的前额叶功能障碍 每一种疾病都与树突棘数量的减少和这一皮层区域的形状改变有关。 我们实验室和其他人的研究表明，慢性压力和糖皮质激素的升高， 下丘脑-垂体-肾上腺应激轴激活的产物，诱导以 mPFC的树突棘缺失和前额叶认知功能受损。虽然取得了一些进展 在阐明动物前额叶可塑性受损的生化和遗传成分方面， 精神疾病的模型，需要更多的工作来确定这些细胞机制 这些变化有助于开发治疗干预的目标。在这方面，最近的考虑是 考虑到线粒体缺陷可能导致慢性应激诱导的认知功能障碍， 损伤和人类精神障碍的发病机制。A-激酶锚定蛋白1（AKAP 1）是一种 将蛋白激酶A（PKA）募集到线粒体外膜的线粒体支架蛋白 导致线粒体分裂蛋白，动力蛋白相关蛋白1的磷酸化和失活 （Drp1）.我们先前已经表明AKAP 1增加线粒体膜电位，这是一个指标， 细胞通过氧化磷酸化产生ATP的能力，而AKAP 1的缺失导致 皮质神经元线粒体分裂和树突棘缺失。这些观察的结果是， 慢性应激引起的前额叶结构和功能改变 可塑性是由mPFC神经元中AKAP 1信号传导减弱介导的。因此，这一目标 探索性/发育性R21是检查AKAP 1在慢性应激诱导的树突棘丢失中的作用 和mPFC神经元的功能妥协，从而为未来的R 01开发数据集。在目标1中， 询问CVS对前额叶树突棘结构的不利影响是否伴随AKAP 1 缺失、Drp 1去磷酸化/激活和线粒体片段化。Aim 2将使用AKAP 1 KO小鼠， 野生型和PKA结合缺陷型AKAP 1的慢病毒递送以鉴定信号传导机制 解释了前额叶线粒体、树突棘和行为改变的破坏。长期 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， 重度抑郁症

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.