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：
8923343
负责人：
Dane M Chetkovich
金额：
$ 18.56万
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 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8923343
关键词：
Adverse effects Antidepressive Agents Behavior Behavioral Assay Biochemical Biological Assay Brain Brain region Cardiac Cells Cessation of life Chemicals Chronic Corticotropin-Releasing Hormone Cyclic Nucleotides Data Dendrites Dependovirus Dopamine Dorsal Doxycycline Economic Burden Effectiveness Electroconvulsive Therapy Electroencephalogram Engineering Epilepsy Evaluation Family Functional disorder Future Genes Genetic Goals Green Fluorescent Proteins Health 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 behavioral study brain pathway cyclic-nucleotide gated ion channels depressed patient 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 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 (MDD) 患者患有药物治疗难治性抑郁症，并且与高残疾率和自杀率相关。大多数 MDD 的现有治疗方法都针对涉及单胺能神经递质血清素、去甲肾上腺素和多巴胺的大脑通路。由于治疗耐药率很高，专注于非单胺能机制的新疗法可能会带来重大突破，挽救许多生命。抑郁症患者大脑中发生改变的一个区域是海马体，它也是抗抑郁药作用的重要靶点。在海马体内，一种称为超极化激活环核苷酸门控 (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以越来越高的水平表达，这种亚细胞定位对于 HCN 通道在信号处理中的作用很重要。 HCN 通道定位受到其辅助亚基 TRIP8b（包含四肽重复的 Rab8b 相互作用蛋白）的严格调控。我们的实验室最近表明，HCN 通道亚基的基因缺失会导致小鼠出现抗抑郁药样表型。此外，其他人发现使用抑制性 RNA 减少海马中的 HCN1 会产生类似的抗抑郁作用，这表明 HCN 通道功能可以作为治疗抑郁症的目标。 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副作用。相比之下，使用病毒载体进行解剖学靶向基因治疗具有精确控制基因表达时间和地点的优点。在初步研究中，我们发现，使用腺相关病毒（AAV）对海马进行病毒感染，该病毒被设计用于阻止海马神经元中 HCN 亚基的正常运输（但不包括表达绿色荧光蛋白的对照 AAV），在测试中显着减少了抑郁样行为抗抑郁活性筛查。因此，我们假设病毒载体介导的抑制背侧海马 HCN 通道的基因疗法是治疗抑郁症的有效方法。为了检验这一假设，我们将使用免疫组织化学、生物化学、电生理学和行为学研究来完成以下具体目标：1）确定针对 HCN 通道的病毒基因治疗是否可以在小鼠中产生特异性且持久的抗抑郁样作用，以及 2）确定是否可以针对 HCN 通道的病毒基因治疗可以有效消除遗传和环境抑郁症小鼠模型中的抑郁样行为。总的来说，我们提出的工作将评估一种不同于当前所有疗法的抑郁症新靶点和创新治疗策略，最终目标是将这种疗法转化为针对患有抑郁症的人类患者的未来研究现有治疗方法难以治愈的抑郁症。