Chronic Ethanol and SK2 Potassium Channels

最近的证据表明，乙醇相关的稳态可塑性涉及代偿性增加 在突触NMDA受体，有助于异常过度兴奋后停止消费和 可能是导致酒精依赖者复发率高的渴望的基础。小电导 钙激活钾（SK）通道调节NMDA受体依赖性钙内流 并且是海马依赖性突触可塑性的关键调节剂。这符合 这表明SK2通道和NMDA受体形成了一个调节钙介导的反馈回路， 单独的树突棘初步证据表明表面SK2通道减少 慢性乙醇处理后，导致SK通道-NMDA受体反馈中断 循环.此外，我们已经证明，SK通道的调制可以影响自愿饮酒 行为因此，总体假设是SK2通道有助于酒精相关的可塑性， SK通道的正性调节降低了戒断相关性神经元损伤的严重程度。 过度兴奋和减少酒精摄入。这些研究将检验以下假设：1） 慢性乙醇暴露通过PKA导致SK2通道表达的稳态降低 信号传导，2）SK通道-NMDA受体反馈环的调节可以减少乙醇戒断， 过度兴奋和神经毒性，和3）突触反馈回路的调制将减少自愿 酒精消费。SK2通道的减少和NMDA受体的增加可能代表了一种新的神经递质的产生。 在乙醇过程中，对NMDA受体活性长期降低的常见稳态适应性反应 exposure.此外，SK2通道-NMDA受体钙介导的这种功能性解偶联 反馈回路可能有助于耐受性发展和戒断性过度兴奋。

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.