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

• 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
• 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

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）患者出现药物治疗难治性抑郁症，并与高致残率和自杀率相关。大多数现有的MDD治疗针对的是涉及单胺能神经递质血清素、去甲肾上腺素和多巴胺的脑通路。由于耐药率很高，关注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，这也是抗抑郁药物作用的重要靶点。在海马体中，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的兴奋性。HCN通道介导的电流（Ih）对于处理神经元之间的突触信号至关重要。HCN通道沿神经元树突的长度表达水平越来越高，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通道的定位受到其辅助亚基TRIP8b（含rab8b的四肽重复相互作用蛋白）的严格调控。我们的实验室最近发现，HCN通道亚基的基因缺失导致小鼠出现抗抑郁样表型。此外，其他研究发现，使用抑制性RNA减少海马中的HCN1也能产生类似的抗抑郁作用，这表明HCN通道功能可以靶向治疗抑郁症。HCN通道对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意想不到的副作用。相比之下，使用病毒载体的解剖学靶向基因治疗提供了精确控制基因表达的时间和地点的好处。在初步研究中，我们发现，在筛选抗抑郁活性的测试中，使用腺相关病毒（AAV）对海马进行病毒感染，以阻止海马神经元中HCN亚基的正常运输（但不控制表达绿色荧光蛋白的AAV），可以显著减少抑郁样行为。因此，我们假设病毒载体介导的基因治疗抑制海马背侧HCN通道是一种有效的抑郁症治疗方法。为了验证这一假设，我们将通过免疫组织化学、生化、电生理和行为学研究来完成以下具体目标：1)确定靶向HCN通道的病毒基因治疗是否能在小鼠中产生特异性和持久的抗抑郁样作用；2)确定靶向HCN通道的病毒基因治疗是否能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新的目标和创新的治疗策略，不同于所有现有的治疗方法，最终目标是将这种治疗方法转化为未来的人类抑郁症患者的研究