The role of somatostatin-expressing GABAergic interneurons in depressive behavior

表达生长抑素的 GABA 能中间神经元在抑郁行为中的作用

• 批准号: 9328360
• 负责人: Sarah Jefferson
• 金额: $ 3.05万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9328360
• 关键词: Affect; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Behavior; Biochemical; Biochemical Markers; Brain; Brain region; Cells; Chronic; Chronic stress; Clinical; Dendrites; Depressed mood; Depressive disorder; Disease; Disease remission; Disinhibition; Distal; Dose; Drug effect disorder; Economic Burden; Epitopes; Functional disorder; Genetic Translation; Genotype; Goals; Hippocampus (Brain); Human; Hyperactive behavior; Immunohistochemistry; Impairment; Interneurons; Ketamine; Major Depressive Disorder; Medial; Mental Depression; Messenger RNA; Molecular; Morbidity - disease rate; Mus; Neurons; Neuropeptides; Neurotransmitters; Pathology; Pathway interactions; Patients; Peptide Elongation Factor 2; Pharmacotherapy; Phenotype; Phosphorylation; Play; Polyribosomes; Population; Prefrontal Cortex; Process; Proteins; Pyramidal Cells; Reverse Transcriptase Polymerase Chain Reaction; Ribosomes; Risk Factors; Rodent; Role; Somatostatin; Stress; Suggestion; Synapses; Synaptic Transmission; Syndrome; Tissue Extracts; Transcript; Transgenic Mice; Translating; Translations; Treatment Efficacy; United States; Western Blotting; anxious; base; depressed patient; depression model; depressive behavior; depressive symptoms; gamma-Aminobutyric Acid; ineffective therapies; interest; neurotransmission; new therapeutic target; novel; receptor; resilience; transcriptome sequencing; transmission process; years lived with disability

Project Summary/Abstract Major Depressive Disorder (MDD) is a highly prevalent and debilitating psychiatric syndrome marked by depressed mood and lack of interest. Stress is an important risk factor for MDD and often precipitates depressive episodes. Current antidepressant drugs require several weeks of treatment to achieve therapeutic efficacy and most patients do not achieve remission with the first antidepressant prescribed. These limitations of current antidepressant drugs highlight the need for a better understanding of the pathophysiology of MDD and identification of novel therapeutic targets. Clinical evidence suggests that MDD is associated with reduced concentrations of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in certain brain regions and reduced expression of GABAA receptors (GABAARs). Somatostatin (SST), a neuropeptide marker of a major subset of primarily dendrite-targeting GABAergic interneurons, is also reduced in certain brain regions of depressed patients. Reducing GABAergic synaptic transmission in mice by heterozygously deleting the γ2 subunit of GABAARs results in an anxious-depressive-like phenotype that includes HPA axis hyperactivity and is normalized by treatment with currently used antidepressants as well as subanesthetic doses of ketamine. Given these findings, we predicted that disinhibition of SST-positive (SST+) GABAergic interneurons through deletion of the γ2 subunit of GABAARs selectively in these neurons (SSTCre:γ2f/f) would result in an antidepressant-like phenotype. Indeed, these mice show reduced depression-related behavior as well as reduced anxiety, along with enhanced GABAergic input to principal cells. Preliminary biochemical analyses of extracts from the hippocampus and medial prefrontal cortex (mPFC) of SSTCre:γ2f/f mice further show reduced phosphorylation of eukaryotic elongation factor 2 (eEF2), consistent with corresponding changes in eEF2 phosphorylation upon treatment of rodents with three different classes of antidepressant drugs and suggestive of enhanced dendritic translation. Based on these findings we hypothesize that enhanced protein translation, particularly in dendrites of principal cells in the hippocampus and mPFC, may underlie the phenotype of SSTCre:γ2f/f mice that mimics antidepressant drug treatment. The goal of this study is to determine whether SSTCre:γ2f/f mice are resilient to unpredictable chronic mild stress (UCMS)-induced depressive behavior and to investigate the molecular mechanism underlying their anxiolytic and antidepressant-like phenotype. To this end, we will cross SSTCre:γ2f/f mice and γ2f/f controls with a line of transgenic mice that express an epitope-tagged ribosomal subunit selectively in pyramidal cells of the hippocampus. This will allow us to isolate polysome-associated mRNAs from principal cells. RNAseq analysis of these mRNAs will then be used to identify transcripts that are differentially translated in SSTCre:γ2f/f versus γ2f/f mice, either at baseline or following UCMS, with the hope of identifying novel candidate protein targets suitable for antidepressant drug therapies.

项目摘要/摘要 严重抑郁障碍(MDD)是一种高度流行和衰弱的精神综合征，其特点是 情绪低落，缺乏兴趣。压力是MDD的一个重要风险因素，通常会导致 抑郁发作。目前的抗抑郁药物需要几周的治疗才能达到治疗效果 大多数患者在开出第一种抗抑郁药后并不能获得缓解。这些限制 目前的抗抑郁药物强调需要更好地了解MDD的病理生理学和 确定新的治疗靶点。 临床证据表明，MDD与抑制性神经递质浓度降低有关 γ-氨基丁酸(GABA)在特定的脑区和GABA受体(GAAA受体)的表达减少。 生长抑素(SST)，主要针对树突状细胞的GABA能主要亚群的神经肽标志物 中间神经元，在抑郁症患者的某些大脑区域也会减少。减少GABA能突触 通过杂合缺失GABAARs的γ2亚单位在小鼠中传播导致焦虑抑郁样 包括HPA轴多动的表型，通过目前使用的治疗而正常化 抗抑郁药以及亚麻醉剂的氯胺酮。考虑到这些发现，我们预测去抑制 选择性缺失GABA受体γ_2亚基对Sst阳性GABA能中间神经元的影响 这些神经元(SSTCre：γ2f/f)将导致抗抑郁药样表型。事实上，这些小鼠表现出减少了 与抑郁相关的行为以及减少焦虑，以及增强对主细胞的GABA能输入。 大鼠海马区和内侧前额叶皮质提取物的生化初步分析 SSTCre：γ2f/f小鼠进一步显示真核细胞延伸因子2(EEF2)的磷酸化降低，与 三种不同类型啮齿动物处理后eEF2磷酸化的相应变化 抗抑郁药物和提示增强树突状细胞的翻译。基于这些发现，我们假设 这增强了蛋白质的翻译，特别是在海马主细胞和mPFC的树突中，可能 SSTCre：γ2f/f小鼠的表型模仿抗抑郁药物治疗。 这项研究的目的是确定SSTCre：γ2f/f小鼠是否对不可预测的慢性轻度应激具有弹性 UCMS诱导的抑郁行为及其抗焦虑的分子机制 和抗抑郁药样表型。为此，我们将用SSTCre：γ2f/f小鼠和γ2f/f对照小鼠 在小鼠锥体细胞中选择性表达表位标记的核糖体亚单位的转基因小鼠 海马体。这将使我们能够从主细胞中分离出多聚体相关的mRNAs。RNASeq分析 然后，这些mRNA将被用于识别在SSTCre中差异翻译的转录本：γ2f/f与γ2f/f 小鼠，无论是在基线还是在UCMS之后，希望找到适合的新的候选蛋白质靶点 用于抗抑郁药物治疗。