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Study of the Functions and Activities of Neuronal K-Cl Co-Transporter KCC2 Using Western Blotting

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Small conductance calcium-activated potassium type 2 channels regulate alcohol-associated plasticity of glutamatergic

Patrick J Mulholland¹, Howard C Becker, John J Woodward

¹Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425-2508, USA.

Biological Psychiatry

|November 9, 2010

Abstract

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.

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