Chronic Ethanol and SK2 Potassium Channels

描述（由申请人提供）：本申请要求支持一个全面的培训计划，该计划将使帕特里克·穆赫兰博士能够拓宽、增强和完善他的技术技能，这是一个富有成效的独立研究生涯所必需的。穆赫兰博士将在导师团队的指导下接受多方面的培训，包括细胞和分子生物学、电生理学以及乙醇依赖和戒断的动物模型。在独立阶段提出的研究计划建立在这种训练的基础上，并更具体地关注于在分子水平上理解与慢性乙醇相关的神经可塑性变化。最近的证据表明，乙醇相关的内稳态可塑性涉及突触NMDA受体代偿性增加，这有助于在停止饮酒时产生异常的高兴奋性，并可能是导致酒精依赖个体高复发发生率的渴望的基础。小电导钙活化钾（SK）通道调节NMDA受体依赖的钙内流，是海马依赖的突触可塑性的关键调节剂。这与SK2通道和NMDA受体在单个树突棘内形成钙介导的调节反馈回路的建议是一致的。初步证据表明，慢性乙醇处理后，表面SK2通道减少。因此，总体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。这些研究将验证以下假设：1)慢性乙醇暴露会导致SK2通道表达和功能的稳态降低，特别是在树突棘中；2)慢性乙醇暴露后SK2通道运输的亚细胞变化是由PKA信号介导的；3)在乙醇依赖的动物模型中，SK通道的调节将防止多重戒断诱导的点燃。SK2通道的减少和NMDA受体的增加可能代表了乙醇暴露期间NMDA受体活性长期降低的共同稳态适应性反应。此外，SK2通道- nmda受体钙介导的反馈回路的这种功能性解耦可能有助于耐受性的发展和戒断性高兴奋性。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稳态可塑性领域的独立研究。

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.