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

Biol Psychiatry. 2011 Apr 1;69(7):625-32. doi: 10.1016/j.biopsych.2010.09.025. Epub 2010 Nov 5.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Benzimidazoles / therapeutic use
  • Calcium / pharmacology
  • Calcium Channel Agonists / therapeutic use
  • Central Nervous System Depressants / adverse effects
  • Central Nervous System Depressants / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Ethanol / adverse effects
  • Ethanol / pharmacology*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Gene Expression Regulation / drug effects
  • Glutamic Acid / metabolism*
  • Glutamic Acid / pharmacology
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Male
  • Mice
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / physiology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology
  • Organ Culture Techniques
  • Patch-Clamp Techniques / methods
  • Propidium / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Small-Conductance Calcium-Activated Potassium Channels / physiology*
  • Substance Withdrawal Syndrome / pathology
  • Substance Withdrawal Syndrome / physiopathology
  • Synapses / drug effects
  • Synapses / metabolism*
  • Time Factors

Substances

  • Benzimidazoles
  • Calcium Channel Agonists
  • Central Nervous System Depressants
  • NR1 NMDA receptor
  • NR2A NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Small-Conductance Calcium-Activated Potassium Channels
  • Propidium
  • Ethanol
  • Glutamic Acid
  • 1-ethyl-2-benzimidazolinone
  • Calcium