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 缺乏会改变前额皮质的多巴胺敏感性摘要精神分裂症是一种毁灭性的精神综合症，影响多达 1% 的人口。了解这种疾病的病理生理过程对于改善治疗至关重要。最近，AKT 信号通路的损伤与精神分裂症的病理生理学有关。尽管已知 AKT 对于多巴胺能传递以维持前额皮质的正常功能非常重要，但 AKT 损伤是否以及如何影响多巴胺系统尚不清楚。该提案旨在利用电生理学和生物化学相结合的方法来检验我们的假设，即皮质 AKT 缺陷通过 β-抑制蛋白 2 介导的机制改变多巴胺敏感性。我们将首先研究 AKT 的破坏是否以及如何改变多巴胺对 PFC 中抑制性突触传递的敏感性。我们将研究在药理学阻断和 RNA 干扰敲低 AKT 的条件下，抑制性突触传递对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发生转变。接下来，我们将探讨 AKT 缺陷引起的多巴胺敏感性转变的机制。我们假设 AKT 缺陷将通过破坏蛋白质复合物来改变 β-arrestin 的亲和力，从而影响多巴胺敏感性。我们将首先通过检查多巴胺受体的表面数量来探讨 AKT 缺乏是否会增加多巴胺受体的内化。然后，我们将测试 AKT 缺陷引起的多巴胺敏感性降低是否会随着 β-arrestin 2 的丢失而改变。接下来，我们将测试 AKT 缺陷引起的 DA 敏感性降低是否与 β-arrestin 2 磷酸化或蛋白质水平的变化有关最后，我们将检查 AKT 缺乏是否会增强 β-视紫红质抑制蛋白 2 与网格蛋白和多巴胺受体的相互作用。该提案将为更好地理解功能与精神障碍相关的神经元之间突触通讯的多巴胺能调节提供新的信息。