Chronic Ethanol and SK2 Potassium Channels

最近的证据表明，酒精相关的体内平衡可塑性涉及代偿性增加。 在突触NMDA受体中，这种受体在停止消费时导致异常的过度兴奋 可能是导致酒精依赖者复发的高发生率的渴望的基础。小电导 钙激活钾(SK)通道调节NMDA受体依赖性钙内流 它们是海马区依赖突触可塑性的关键调节因子。这与 提示SK2通道和NMDA受体在体内形成一个调节的钙调节反馈环 单独的树枝状刺。初步证据显示表面SK2通道减少 慢性乙醇治疗导致SK通道-NMDA受体反馈中断 循环播放。此外，我们还证明了SK通道的调节可以影响自愿饮酒 行为。因此，最重要的假设是SK2通道有助于酒精相关的可塑性 谷氨酸能突触和SK通道正向调制减轻戒断相关的严重程度 过度兴奋，减少酒精摄入量。这些研究将检验以下假设：1) 慢性酒精暴露通过PKA导致SK2通道表达的稳态降低 信号转导，2)调节SK通道-NMDA受体反馈环可以减少酒精戒断， 过度兴奋性和神经毒性，以及3)突触反馈回路的调节将降低自愿性 饮酒。SK2通道的减少和NMDA受体的增加可能代表 常见的稳态适应性反应对酒精期间NMDA受体活性的长期降低 曝光。此外，这种SK2通道-NMDA受体的功能解偶联是由钙介导的 反馈环可能有助于耐受性的发展和戒断的过度兴奋。

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 that leads to a disruption of the SK channel-NMDA receptor feedback loop. Moreover, we have demonstrated that modulation of SK channels can influence voluntary drinking behavior. Thus, the overarching hypothesis is that SK2 channels contribute to alcohol-associated plasticity of glutamatergic synapses and that positive modulation of SK channels reduces the severity of withdrawal-related hyperexcitability and decreases alcohol intake. These studies will test the hypotheses that: 1) chronic ethanol exposure produces a homeostatic reduction in SK2 channel expression through PKA signaling, 2) modulation of the SK channel-NMDA receptor feedback loop can reduce ethanol withdrawal , hyperexcitability and neurotoxicity, and 3) modulation of the synaptic feedback loop will reduce voluntary alcohol consumption. 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.