Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425-2508, USA.
Biol Psychiatry. 2011 Apr 1;69(7):625-32. doi: 10.1016/j.biopsych.2010.09.025. Epub 2010 Nov 5.
Small conductance calcium-activated potassium type 2 channels (SK2) control excitability and contribute to plasticity by reducing excitatory postsynaptic potentials. Recent evidence suggests that SK2 channels form a calcium-dependent negative-feedback loop with synaptic N-methyl-D-aspartate (NMDA) receptors. Addiction to alcohol and other drugs of abuse induces plastic changes in glutamatergic synapses that include the targeting of NMDA receptors to synaptic sites; however, the role of SK2 channels in alcohol-associated homeostatic plasticity is unknown.
Electrophysiology, Western blot, and behavioral analyses were used to quantify changes in hippocampal small conductance calcium-activated potassium (SK) channel function and expression using well-characterized in vitro and in vivo models of chronic alcohol exposure.
Chronic ethanol reduced apamin-sensitive SK currents in cornu ammonis 1 pyramidal neurons that were associated with a downregulation of surface SK2 channels. Blocking SK channels with apamin potentiated excitatory postsynaptic potentials in control but not ethanol-treated cornu ammonis 1 pyramidal neurons, suggesting that chronic ethanol disrupts the SK channel-NMDA receptor feedback loop. Alcohol reduced expression of SK2 channels and increased expression of NMDA receptors at synaptic sites in a mouse model. Positive modulation of SK function by 1-EBIO decreased alcohol withdrawal hyperexcitability and attenuated ethanol withdrawal neurotoxicity in hippocampus. The 1-EBIO also reduced seizure activity in mice undergoing withdrawal.
These results provide evidence that SK2 channels contribute to alcohol-associated adaptive plasticity of glutamatergic synapses and that positive modulation of SK channels reduces the severity of withdrawal-related hyperexcitability. Therefore, SK2 channels appear to be critical regulators of alcohol-associated plasticity and may be novel therapeutic targets for the treatment of addiction.
小电导钙激活钾通道 2 型（SK2）通过减少兴奋性突触后电位来控制兴奋性并促进可塑性。最近的证据表明，SK2 通道与突触 N-甲基-D-天冬氨酸（NMDA）受体形成钙依赖性负反馈回路。酒精和其他滥用药物成瘾会导致谷氨酸能突触发生可塑性变化，包括 NMDA 受体向突触部位的靶向；然而，SK2 通道在酒精相关的稳态可塑性中的作用尚不清楚。
使用电生理学、Western blot 和行为分析，使用经过充分表征的体外和体内慢性酒精暴露模型，定量研究海马小电导钙激活钾（SK）通道功能和表达的变化。
慢性乙醇降低了 CA1 锥体神经元中阿米巴敏感的 SK 电流，这与表面 SK2 通道的下调有关。用阿米巴素阻断 SK 通道增强了对照但不是乙醇处理的 CA1 锥体神经元中的兴奋性突触后电位，表明慢性乙醇破坏了 SK 通道-NMDA 受体反馈回路。酒精在突触部位减少了 SK2 通道的表达，增加了 NMDA 受体的表达在小鼠模型中。1-EBIO 对 SK 功能的正调控降低了海马中的酒精戒断过度兴奋，并减轻了乙醇戒断神经毒性。1-EBIO 还减少了正在戒断的小鼠的癫痫发作活动。
这些结果提供了证据表明，SK2 通道有助于谷氨酸能突触与酒精相关的适应性可塑性，而 SK 通道的正调控可降低与戒断相关的过度兴奋的严重程度。因此，SK2 通道似乎是酒精相关可塑性的关键调节剂，可能是治疗成瘾的新的治疗靶点。
