AKT deficiency alters dopamine sensitivity in the prefrontal cortex

AKT 缺乏会改变前额皮质的多巴胺敏感性

基本信息

批准号：
8828790
负责人：
Yan-Chun Li
金额：
$ 7.83万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828790
关键词：
AKT Signaling Pathway AKT inhibition AKT1 gene ARRB2 Address Affect Affinity Attention Behavior Biochemistry Clathrin Communication Cyclic AMP DARPP Depressed mood Disease Dopamine Dopamine Agonists Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Dose Electrophysiology (science)Experimental Designs Functional disorder GTP-Binding Proteins Glycogen Synthase Kinase 3 Goals Health Human Impairment Investigation Mediating Mental disorders Mutant Strains Mice Neurons Pathway interactions Patients Phosphorylation Play Population Prefrontal Cortex Process Protein Kinase Protein phosphatase Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt RNA Interference Regulation Role Scaffolding Protein Schizophrenia Short-Term Memory Signal Pathway Signal Transduction Specificity Surface Synapses Synaptic Transmission Syndrome Testing Yang attenuation beta-arrestin cognitive function depressive symptoms desensitization dopamine system improved inhibitor/antagonist novel protein complex receptor receptor function receptor internalization receptor sensitivity response transmission process

项目摘要

DESCRIPTION (provided by applicant): AKT deficiency alters dopamine sensitivity in the prefrontal cortex ABSTRACT Schizophrenia is a devastating psychiatric syndrome that affects up to 1% of the human population. Understanding the pathophysiological processes underlying this disease is essential for improving treatment. Recently, impairment of the AKT signaling pathway has been implicated in the pathophysiology of schizophrenia. Although AKT is known to be important for dopaminergic transmission to maintain normal functioning of the prefrontal cortex, whether and how impairment of AKT affects the dopamine system are not clearly understood. Using an approach integrating electrophysiology and biochemistry, this proposal seeks to examine our hypothesis that cortical AKT deficiency alters dopamine sensitivity by beta-arrestin 2-mediated mechanisms. We will first examine whether and how disruption of AKT changes dopamine sensitivity to inhibitory synaptic transmission in the PFC. We will examine the responses inhibitory synaptic transmission to different concentrations of dopamine or different types of dopamine receptor agonists under conditions of pharmacologic blockage and RNA interference knockdown of AKT. We predict a shift of dopamine sensitivity to inhibitory synaptic transmission. Next, we will explore the mechanisms underlying the AKT deficiency-induced shifting of dopamine sensitivity. We hypothesize that AKT deficiency will alter the affinity of beta-arrestin by disrupting the protein complexes, thus affecting dopamine sensitivity. We will first explore whether AKT deficiency increases dopamine receptor internalization by examining surface number of dopamine receptors. We will then test whether AKT deficiency-induced decrease in dopamine sensitivity changes with loss of beta- arrestin 2. Next, we will test whether AKT deficiency-induced decrease in DA sensitivity is involved in changes in phosphorylation or protein level of beta-arrestin 2. Finally, we will examine whether interaction of beta- arrestin 2 with clathrin and dopamine receptors is enhanced by AKT deficiency. This proposal will offer novel information for a better understanding of dopaminergic regulation of synaptic communication between neurons whose functioning is related to mental disorders.

描述（由申请人提供）：AKT缺乏症改变了前额叶皮质中的多巴胺敏感性抽象精神分裂症是一种毁灭性的精神病综合症，可影响多达1％的人群。了解该疾病的基础病理生理过程对于改善治疗至关重要。最近，AKT信号通路的损害与精神分裂症的病理生理有关。尽管已知AKT对于多巴胺能传播至关重要，以维持前额叶皮层的正常功能，但AKT的损害是否以及如何影响多巴胺系统。该提案使用整合电生理学和生物化学的方法，试图研究我们的假设，即皮质Akt缺乏症可以通过β-arrestin 2介导的机制改变多巴胺的敏感性。我们将首先研究AKT的破坏以及如何改变对PFC中抑制性突触传播的敏感性。我们将在药理阻塞和AKT的RNA干扰敲低的条件下检查不同浓度的多巴胺或不同类型的多巴胺受体激动剂的反应。我们预测多巴胺对抑制性突触传递的敏感性会转移。接下来，我们将探讨Akt缺乏引起的多巴胺敏感性转移的基础机制。我们假设Akt缺乏会通过破坏蛋白质复合物来改变β-arrestin的亲和力，从而影响多巴胺的敏感性。我们将首先探讨AKT缺乏是否通过检查多巴胺受体的表面数来增加多巴胺受体的内在化。 We will then test whether AKT deficiency-induced decrease in dopamine sensitivity changes with loss of beta- arrestin 2. Next, we will test whether AKT deficiency-induced decrease in DA sensitivity is involved in changes in phosphorylation or protein level of beta-arrestin 2. Finally, we will examine whether interaction of beta- arrestin 2 with clathrin and dopamine receptors is enhanced by AKT deficiency.该建议将提供新的信息，以更好地了解与精神障碍有关的神经元之间突触沟通的多巴胺能调节。