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.
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425-2508, USA.
Patrick J
PJ
Mulholland
Howard C
HC
Becker
John J
JJ
Woodward
L Judson
LJ
Chandler
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000627:therapeutic use; D002118:Calcium / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000627:therapeutic use; D002492:Central Nervous System Depressants / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques / Q000379:methods; D011419:Propidium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000473:pathology / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
D001562:Benzimidazoles; D002120:Calcium Channel Agonists; D002492:Central Nervous System Depressants; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D051640:Small-Conductance Calcium-Activated Potassium Channels; D011419:Propidium; D000431:Ethanol; D018698:Glutamic Acid; C102635:1-ethyl-2-benzimidazolinone; D002118:Calcium