Role of HCN Channels in Major Depressive Disorder Etiology and Treatment

 在美国，到75岁时，有四分之一的人有患抑郁症的风险，到2030年，抑郁症将成为全球疾病负担的主要原因之一。在过去的五年中，抑郁症的治疗一直由影响一组称为“单胺”的分子的药物主导，其中血清素是最常见的目标。虽然对某些人有效（30-50%），但那些仍然没有缓解的人几乎没有治疗选择，因为很难找到新的药物策略。在过去的几十年里，越来越明显的是，大脑活动和连接的变化严重影响了抑郁症的发展。具体来说，海马体，一个对情绪和记忆很重要的大脑区域，已经被证明是抑郁症发展的组成部分。我们的实验室研究大脑中一种独特的蛋白质，称为超极化激活的环核苷酸门控通道（HCN），它有助于调节细胞之间的电流。通过这样做，该通道在巩固和维持单个神经元之间的连接，最终，整个大脑区域之间的连接方面发挥了不可或缺的作用。最近，我们和其他人发现，海马体中这些通道的缺失在小鼠中具有明显的抗抑郁作用。鉴于这一发现，我们建议研究HCN在抑郁症的发展和治疗中的作用，并假设HCN通道随着抑郁样行为的增加而增加，HCN通道的减少与抑郁样行为的减少相关。具体而言，我们假设HCN随着慢性应激小鼠的抑郁样行为而增加（Aim 1），HCN亚基敲除保护应激小鼠免受抑郁样行为（Aim 2.1），海马中HCN亚基的病毒过表达增加抑郁样行为（Aim 2.2），抗抑郁药减少HCN亚基（Aim 3）。

 DESCRIPTION (provided by applicant): In the United States, there is a 1 in 4 risk of developing depression by age 75, and by 2030 depression will be one of the leading causes of disease burden world-wide. For the past half-decade, the treatment of depression has been dominated by drugs that affect a group of molecules called the "monoamines," with serotonin being the most commonly targeted. While effective for some people (30-50%), those that remain without relief have few options for therapy, as newer drug strategies have been hard to come by. Within the last few decades, it has become more and more apparent that changes in the activity and connections within the brain heavily influence the development of depression. Specifically, the hippocampus, a brain region important for emotion and memory, has been shown to be integral to depression's development. Our lab studies a unique protein in the brain called the Hyperpolarization-activated Cyclic-Nucleotide gated channel (HCN), which helps to regulate the flow of electricity from cell to cell. By doing this, the channel has an integral rolein solidifying and maintaining the connections between individual neurons and, ultimately, whole brain regions. Recently, we and others showed that a loss of these channels in the hippocampus has a distinct antidepressant-like effect in mice. Given this finding, we propose to study the roles of HCN in the development and treatment of depression, and hypothesize that HCN channels increase with depression-like behavior, and reduction of HCN channels correlate with a reduction in depression-like behavior. Specifically, we hypothesize that HCN is increased with depression-like behavior in chronically stressed mice (Aim1), that HCN subunit knock- out protects stressed mice from depression-like behavior (Aim 2.1), viral overexpression of HCN subunits in the hippocampus increase depression-like behavior (Aim 2.2), and antidepressants decrease HCN subunits (Aim 3).