Synergistic roles of GABAA receptors and SK channels in regulating thalamocortical oscillations.
Rhythmic oscillations throughout the cortex are observed during physiological and pathological states of the brain. The thalamus generates sleep spindle oscillations and spike-wave discharges characteristic of absence epilepsy. Much has been learned regarding the mechanisms underlying these oscillations from in vitro brain slice preparations. One widely used model to understand the epileptiform oscillations underlying absence epilepsy involves application of bicuculline methiodide (BMI) to brain slices containing the thalamus. BMI is a well-known GABAA receptor blocker that has previously been discovered to also block small-conductance, calcium-activated potassium (SK) channels. Here we report that the robust epileptiform oscillations observed during BMI application rely synergistically on both GABAA receptor and SK channel antagonism. Neither application of picrotoxin, a selective GABAA receptor antagonist, nor application of apamin, a selective SK channel antagonist, alone yielded the highly synchronized, long-lasting oscillations comparable to those observed during BMI application. However, partial blockade of SK channels by subnanomolar concentrations of apamin combined with picrotoxin sufficiently replicated BMI oscillations. We found that, at the cellular level, apamin enhanced the intrinsic excitability of reticular nucleus (RT) neurons but had no effect on relay neurons. This work suggests that regulation of RT excitability by SK channels can influence the excitability of thalamocortical networks and may illuminate possible pharmacological treatments for absence epilepsy. Finally, our results suggest that changes in the intrinsic properties of individual neurons and changes at the circuit level can robustly modulate these oscillations.
Kleiman-Weiner
Max
M
Department of Biological Sciences, Rm. M030 Alway Bldg., Stanford University, School of Medicine, Stanford, CA 94305-5122, USA.
Beenhakker
Mark P
MP
Segal
William A
WA
Huguenard
John R
JR
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001030:Apamin / Q000494:pharmacology; D001640:Bicuculline / Q000031:analogs & derivatives / Q000494:pharmacology; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004558:Electric Stimulation / Q000379:methods; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D010852:Picrotoxin / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D013788:Thalamus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D001030:Apamin; D001640:Bicuculline; D018756:GABA Antagonists; D010852:Picrotoxin; D026902:Potassium Channel Blockers; D011963:Receptors, GABA-A; D051640:Small-Conductance Calcium-Activated Potassium Channels; C017069:bicuculline methiodide