Chronic Ethanol and SK2 Potassium Channels

描述(由申请者提供)：此申请请求支持一项全面的培训计划，该计划将使Patrick Mulholland博士能够拓宽、增强和完善他的技术技能，这些技能是他富有成效的独立研究生涯所必需的。在该奖项的指导阶段，穆赫兰博士将接受一个合作导师团队的多方面培训，其中包括细胞和分子生物学、电生理学以及酒精依赖和戒断的动物模型方面的培训。在独立阶段提出的研究计划建立在这一培训的基础上，并更具体地侧重于在分子水平上了解与慢性乙醇相关的神经可塑性变化。最近的证据表明，酒精相关的稳态可塑性涉及突触NMDA受体的代偿性增加，这种受体在停止饮酒时导致异常的过度兴奋，并可能是导致酒精依赖者复发的渴望的基础。小电导钙激活钾(SK)通道调节NMDA受体依赖性钙内流，是海马依赖性突触可塑性的重要调节器。这与SK2通道和NMDA受体在单个树突棘内形成调节钙介导的反馈环路的说法是一致的。初步证据表明，慢性乙醇处理后，表面SK2通道减少。因此，最重要的假设是，慢性乙醇暴露导致SK2通道-NMDA受体反馈回路的稳态功能解偶联。这些研究将检验以下假设：1)慢性酒精暴露导致SK2通道表达和功能的稳态下降，特别是在树突棘内；2)慢性乙醇后SK2通道运输的亚细胞变化是由PKA信号介导的；3)SK通道的调节将防止多次戒断诱导的酒精依赖动物模型点燃。SK2通道的减少和NMDA受体的增加可能是一种常见的对酒精暴露期间NMDA受体活性长期降低的动态平衡适应性反应。此外，SK2通道-NMDA受体钙调节反馈环路的这种功能解偶联可能有助于耐受的发展和戒断的过度兴奋。此外，这些研究的结果将有助于指导穆赫兰博士未来在乙醇相关的体内平衡可塑性领域的独立研究。 公共卫生相关性：这些研究的结果将提供对中枢神经系统酒精相关变化潜在机制的洞察，并可能确定一种新的治疗靶点，以减少对酒精的渴望，防止高复发率。

DESCRIPTION (provided by applicant): This application requests support for a comprehensive training plan that will enable Patrick Mulholland, Ph.D. to broaden, enhance, and refine his technical skills that are necessary for a productive independent research career. Dr. Mulholland will receive multifaceted training during the mentored phase of the award from a team of collaborating mentors that includes training in cellular and molecular biology, electrophysiology, and animal models of ethanol dependence and withdrawal. The research plan that is proposed during the independent phase builds on this training and focuses more specifically on understanding neuroplastic changes associated with chronic ethanol at the molecular level. Recent evidence suggests that ethanol- associated homeostatic plasticity involves compensatory increases in synaptic NMDA receptors that contributes to aberrant hyperexcitability upon cessation of consumption and may underlie craving that leads to the high incidence of relapse in alcohol dependent individuals. Small-conductance calcium-activated potassium (SK) channels regulate NMDA receptor-dependent calcium influx and are critical modulators of hippocampal-dependent synaptic plasticity. This is consistent with the suggestion that SK2 channels and NMDA receptors form a regulatory calcium-mediated feedback loop within individual dendritic spines. Preliminary evidence demonstrates a reduction in surface SK2 channels following chronic ethanol treatment. Thus, the overarching hypothesis is that chronic ethanol exposure leads to a homeostatic functional uncoupling of the SK2 channel-NMDA receptor feedback loop. These studies will test the hypotheses that: 1) chronic ethanol exposure produces a homeostatic reduction in SK2 channel expression and function, specifically within dendritic spines, 2) the subcellular change in SK2 channel trafficking following chronic ethanol is mediated by PKA signaling, and 3) modulation of SK channels will prevent multiple withdrawal-induced kindling in an animal model of ethanol dependence. Decreases in SK2 channels and increases in NMDA receptors may represent a common homeostatic adaptive response to prolonged reductions in NMDA receptor activity during ethanol exposure. Furthermore, this functional uncoupling of the SK2 channel-NMDA receptor calcium-mediated feedback loop may contribute to tolerance development and to withdrawal hyperexcitability. In addition, results from these studies will serve to guide Dr. Mulholland's future independent research in the area of ethanol-associated homeostatic plasticity. PUBLIC HEALTH RELEVANCE: Findings from these studies will provide insight into the mechanisms underlying ethanol-associated changes in the central nervous system and may identify a novel therapeutic target to reduce craving for alcohol and prevent the high incidence of relapse.