Small Conductance Calcium-Activated Potassium Type 2 Channels Regulate Alcohol-Associated Plasticity of Glutamatergic Synapses

Background: 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. Methods: 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. Results: 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. Conclusions: 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.