Evaluation of antidepressant-like effects of hippocampal HCN channel modulation

海马 HCN 通道调节的抗抑郁样作用评价

基本信息

批准号：
8824404
负责人：
Dane M Chetkovich
金额：
$ 22.46万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2014-09-08 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8824404
关键词：
Adverse effects Antidepressive Agents Behavior Behavioral Behavioral Assay Biochemical Biological Assay Brain Brain region Cardiac Cells Cessation of life Chemicals Chronic Corticotropin-Releasing Hormone Cyclic Nucleotides Data Dendrites Dependovirus Depressed mood Dopamine Dorsal Doxycycline Economic Burden Effectiveness Electroconvulsive Therapy Electroencephalogram Engineering Epilepsy Evaluation Family Functional disorder Future Genes Genetic Goals Green Fluorescent Proteins Heart High Prevalence Hippocampus (Brain)Human Impaired cognition Ion Channel Lead Length Major Depressive Disorder Mediating Medical Membrane Proteins Mental Depression Methods Modeling Morbidity - disease rate Mus Neurons Neurotransmitters Norepinephrine Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Play Process Prosencephalon Protein Isoforms Proteins RNA RNA Splicing Reagent Refractory Reporting Resistance Role Seizures Serotonin Signal Transduction Specificity Suicide Synapses Testing Time Transgenic Mice Translating Viral Viral Genes Viral Vector Virus Virus Diseases Work base brain pathway cyclic-nucleotide gated ion channels disability effective therapy gene therapy hippocampal pyramidal neuron innovation knock-down mortality motor impairment mouse model nervous system disorder neuronal excitability novel overexpression prevent promoter public health relevance screening signal processing small hairpin RNA social trafficking treatment strategy treatment-resistant depression

项目摘要

DESCRIPTION (provided by applicant): Depression refractory to medical treatment is seen in over half of patients with Major Depressive Disorder (MDD) and is associated with high rates of disability and suicide. Most existing treatments for MDD target brain pathways involving the monoaminergic neurotransmitters serotonin, norepinephrine and dopamine. Because of high rates of treatment resistance, new therapies focusing on non-monoaminergic mechanisms could lead to major breakthroughs, saving many lives. One region of the brain altered in patients with depression is the hippocampus, which is also an important target for the action of antidepressants. Within the hippocampus, an ion channel called the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel helps control neuronal excitability. HCN channels mediate a current (Ih) that is critical for processing synaptic signals between neurons. The HCN channel is expressed at increasingly higher levels along the length of neuronal dendrites, and this subcellular localization is important for the HCN channel's role in signal processing. HCN channel localization is tightly regulated by its auxiliary subunit, TRIP8b (tetratricopeptide repea-containing Rab8b-interacting protein). Our lab recently showed that genetic deletion of HCN channel subunits leads to an antidepressant-like phenotype in mice. Furthermore, others found that decreasing HCN1 in the hippocampus using inhibitory RNA produced similar antidepressant effects, suggesting HCN channel function could be targeted to treat depression. HCN channels are crucial for many functions in the brain and heart, thus pharmaceutical approaches to inhibiting HCN channels could produce unwanted side effects. In contrast, anatomically targeted gene therapy using viral vectors offers the benefit of controlling exactly when and where genes are expressed. In preliminary studies, we found that viral infection of the hippocampus using an adeno-associated virus (AAV) engineered to prevent normal trafficking of HCN subunits in hippocampal neurons (but not control AAV expressing green fluorescent protein) markedly reduced depression-like behavior in tests that screen for antidepressant activity. We thus hypothesize that viral vector-mediated gene therapy to suppress HCN channels in the dorsal hippocampus is an effective treatment for depression. To test this hypothesis, we will use immunohistochemical, biochemical, electrophysiological and behavioral studies to complete the following specific aims: 1) Determine if viral gene therapy targeting HCN channels can produce specific and lasting antidepressant-like effects in mice, and 2) Determine if viral gene therapy targeting HCN channels can effectively eliminate depression-like behaviors in genetic and environmental mouse models of depression. Overall, our proposed work will evaluate a novel target and innovative treatment strategy for depression distinct from all current therapy, with an ultimate goal of translating this therapy to future studies in human patients with depression refractory to existing treatments.

描述（由申请人提供）：超过一半的重度抑郁症患者（MDD）可见治疗的抑郁症对医疗治疗，并且与较高的残疾和自杀率有关。大多数现有的MDD靶向脑途径涉及单胺能神经递质5-羟色胺，去甲肾上腺素和多巴胺的治疗方法。由于耐药性较高，重点关注非单胺能机制的新疗法可能会导致重大突破，从而挽救许多生命。抑郁症患者改变的大脑区域是海马，这也是抗抑郁药作用的重要目标。在海马中，一个称为超极化循环核苷酸门控（HCN）通道的离子通道有助于控制神经元兴奋性。 HCN通道介导一个电流（IH），这对于处理神经元之间的突触信号至关重要。 HCN通道沿着神经元树突的长度越来越高的水平表达，该亚细胞定位对于HCN通道在信号处理中的作用很重要。 HCN通道的定位受其辅助亚基Trip8b（四肽重复的RAB8B相互作用蛋白）的严格调节。我们的实验室最近表明，HCN通道亚基的遗传缺失导致小鼠的抗抑郁样表型。此外，其他人发现，使用抑制性RNA在海马中降低HCN1会产生相似的抗抑郁作用，这表明HCN通道功能可以针对治疗抑郁症。 HCN通道对于大脑和心脏的许多功能至关重要，因此抑制HCN通道的药物方法可能会产生不良的副作用。相比之下，使用病毒载体的解剖学靶向基因治疗具有准确控制基因何时和何时表达基因的好处。在初步研究中，我们发现，使用腺相关病毒（AAV）对海马的病毒感染进行了设计，该病毒（AAV）设计用于防止在海马神经元中正常运输HCN亚基（但不能对照AAV表达绿色荧光蛋白）显着降低了抑郁症的行为，以筛查抗抑郁活性的测试。因此，我们假设病毒载体介导的基因治疗以抑制背侧海马中的HCN通道是抑郁症的有效治疗方法。为了检验该假设，我们将使用免疫组织化学，生化，电生理学和行为研究来完成以下具体目的：1）靶向靶向HCN通道的病毒基因治疗是否可以在小鼠中产生特定的抗抑郁药样效应，并且2）确定病毒基因治疗靶向HCN通道的遗传抑制作用是否可以有效地抑制型抑郁症。总体而言，我们提出的工作将评估与当前所有疗法不同的抑郁症的新型目标和创新治疗策略，其最终目的是将这种疗法转化为未来的研究对现有治疗的抑郁症状。