ASICs in the n. accumbens in depression-related synaptic plasticity and behavior

n 中的 ASIC。

• 批准号: 8967085
• 负责人: John A Wemmie
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967085
• 关键词: ASIC channel; Acidosis; Acids; Amiloride; Animal Model; Animals; Antidepressive Agents; Anxiety; Anxiety Disorders; Architecture; Behavior; Behavioral; Brain; Buffers; Carbonic Anhydrase IV; Chronic; Chronic stress; Complex; Data; Dendritic Spines; Depression and Suicide; Emotional Stress; Enzymes; Epidemiologic Studies; Epithelial; Excitatory Synapse; Family; Fright; GABA Antagonists; General Population; Glutamate Receptor; Glutamates; Goals; Health; Human; Incidence; Ion Channel; Knowledge; Lead; Mediating; Mental Depression; Modeling; Morbidity - disease rate; Morphology; Mus; Neurons; Nucleus Accumbens; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Physiology; Play; Post-Traumatic Stress Disorders; Process; Protons; Refractory; Research Proposals; Role; Signal Transduction; Site; Sodium Channel; Source; Stress; Suicide; Swimming; Synapses; Synaptic Cleft; Synaptic Membranes; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Tail Suspension; Testing; Therapeutic; Veterans; anxiety-related behavior; base; behavioral response; carbonate dehydratase; disability; effective therapy; extracellular; learned behavior; monoamine; mortality; neurotransmission; new therapeutic target; novel; novel therapeutics; public health relevance; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Depression is consistently one of the top causes of morbidity and mortality, and veterans are afflicted more commonly than non-veterans. In addition, veterans are more than twice as likely to die from depression- related suicide than the general population. Despite current antidepressant medications, a disappointingly large number of patients are refractory to current treatments, all of which target similar mechanisms. Thus, new medications with novel mechanisms of action are urgently needed. Using animal models that can predict antidepressant and anti-anxiety effects in humans, we identified a novel molecule in depression and anxiety- related behaviors, the acid-sensing ion channel 1a (ASIC1A). Pharmacologically inhibiting and genetically disrupting ASIC1A in mice produced antidepressant-like effects in the forced swim test, tail suspension test, and following chronic unpredictable stress. Moreover, the effects were independent of and additive to several currently used antidepressant medications. Disrupting ASIC1A also reduced conditioned and unconditioned fear behaviors, which model post-traumatic stress disorder (PTSD) and other anxiety disorders. Together these findings suggest the exciting possibility that targeting ASIC1A will relieve depression and anxiety through a novel mechanism of action. To take full advantage of this possibility we need to know more about how ASIC1A is activated in the brain. The exquisite sensitivity of ASIC1A to low extracellular pH suggests that acidic pH might play an important signaling role. Supporting this possibility, we recently identified a novel current during synaptic transmission in the nucleus accumbens (NAc) that depended on ASIC1A and ASIC2, and was inhibited by the ASIC antagonists amiloride and psalmotoxin. Furthermore, inhibiting or genetically deleting carbonic anhydrase 4 (CA4), a key pH-buffering enzyme in the brain, increased this novel ASIC- dependent synaptic current. Finally, loss of ASIC1A and the associated current was accompanied by significant structural and functional changes at glutamatergic synapses, which we suspect may underlie the behavioral consequences of ASIC disruption. Based on these observations we hypothesize that ASICs and CA4 play key roles in depression-related synaptic physiology in the NAc and depression-related behavior. To test this hypothesis we propose to answer the following questions: 1) Do ASIC1A and ASIC2 contribute to synaptic and behavioral responses to chronic stress? 2) Does carbonic anhydrase 4 contribute to synaptic plasticity in the NAc and depression-related behavior? And, 3) can inhibiting or deleting ASIC1A reverse effects of chronic stress on depression-related behavior, and is the NAc a key site of ASIC1A action? The answers to these questions will provide important steps towards our long-term goals of better understanding the role of ASICs in brain function and behavior and learning to target these processes for therapeutic purposes.

描述（由申请人提供）： 抑郁症一直是发病率和死亡率最高的原因之一，退伍军人比非退伍军人更常见。此外，退伍军人死于抑郁症相关自杀的可能性是普通人群的两倍多。尽管目前有抗抑郁药物，但令人不安的是，大量患者对目前的治疗难以治疗，所有这些治疗都针对类似的机制。因此，迫切需要具有新作用机制的新药物。使用可以预测人类抗抑郁和抗焦虑作用的动物模型，我们确定了抑郁和焦虑相关行为的新分子，酸敏感离子通道1a（ASIC1A）。药理学抑制和遗传破坏ASIC1A在小鼠中产生抗抑郁样作用，在强迫游泳试验，悬尾试验，和以下慢性不可预测的压力。此外，这些作用独立于目前使用的几种抗抑郁药物，并与之叠加。破坏ASIC1A还减少了条件性和非条件性恐惧行为，这是创伤后应激障碍（PTSD）和其他焦虑症的模型。总之，这些发现表明，靶向ASIC1A将通过一种新的作用机制缓解抑郁和焦虑的可能性令人兴奋。为了充分利用这种可能性，我们需要更多地了解ASIC1A在大脑中是如何被激活的。ASIC1A对低细胞外pH的敏感性表明酸性pH可能发挥重要的信号传导作用。支持这种可能性，我们最近确定了一种新的电流在突触传递过程中的神经核（NAc），依赖于ASIC1A和ASIC2，并抑制ASIC拮抗剂阿米洛利和psalmotoxin。此外，抑制或基因删除碳酸酐酶4（CA4），在大脑中的关键pH缓冲酶，增加这种新的ASIC依赖性突触电流。最后，ASIC1A和相关电流的丧失伴随着突触的显著结构和功能变化，我们怀疑这可能是ASIC中断的行为后果的基础。基于这些观察，我们假设ASIC和CA4在NAc和抑郁相关行为中的抑郁相关突触生理学中起关键作用。为了验证这一假设，我们提出回答以下问题：1）ASIC1A和ASIC2有助于突触和行为反应的慢性压力？2)碳酸酐酶4是否有助于NAc和抑郁相关行为的突触可塑性？抑制或删除ASIC1A是否可以逆转慢性应激对抑郁相关行为的影响，NAc是否是ASIC1A作用的关键部位？这些问题的答案将为我们更好地理解ASIC在大脑功能和行为中的作用以及学习将这些过程用于治疗目的的长期目标提供重要步骤。