The role of somatostatin-expressing GABAergic interneurons in depressive behavior

项目总结/摘要 重性抑郁症（MDD）是一种高度流行和使人衰弱的精神综合征，其特征是 情绪低落，缺乏兴趣。压力是MDD的一个重要危险因素， 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。 疗效和大多数患者没有达到缓解与第一个抗抑郁药处方。的这些限制 目前的抗抑郁药物强调需要更好地了解MDD的病理生理学， 新的治疗靶点的鉴定。 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）在某些脑区和GABAA受体（GABAAR）的表达减少。 生长抑素（SST），一种主要靶向树突的GABA能神经肽标记物， 在抑郁症患者的某些大脑区域中也减少了。减少GABA能突触 通过异源性缺失GABAAR γ2亚单位在小鼠中的传递导致焦虑-抑郁样 表型包括HPA轴活动过度，并通过目前使用的 抗抑郁药和亚麻醉剂量的氯胺酮鉴于这些发现，我们预测， SST阳性（SST+）GABA能中间神经元通过选择性缺失GABAARs γ2亚单位， 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的 抑郁相关行为以及焦虑减少，沿着增强的GABA能输入到主细胞。 从海马和内侧前额叶皮质（mPFC）提取的初步生化分析， SSTCre：γ2f/f小鼠进一步显示出真核延伸因子2（eEF 2）的磷酸化降低，与 在用三种不同类型的药物治疗啮齿动物后，eEF 2磷酸化的相应变化 抗抑郁药物和暗示增强树突翻译。基于这些发现，我们假设 增强的蛋白质翻译，特别是在海马和mPFC的主细胞树突中，可能 是模拟抗抑郁药物治疗的SSTCre：γ2f/f小鼠表型的基础。 本研究的目的是确定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，并探讨其抗焦虑的分子机制 和抗抑郁药样表型。为此，我们将SSTCre：γ2f/f小鼠和γ2f/f对照与一系 转基因小鼠，其选择性地在小脑的锥体细胞中表达表位标记的核糖体亚基， 海马体。这将使我们能够从主细胞中分离出多聚体相关的mRNA。RNAseq分析 然后，这些mRNA将用于鉴定在SSTCre中差异翻译的转录物：γ2f/f与γ2f/f 小鼠，无论是在基线或以下UCMS，希望确定新的候选蛋白质的目标， 用于抗抑郁药物治疗。

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.