Modulation of epileptiform activity by activation of tonic inhibition
Open Access
- Author:
- Pitre, Anar
- Graduate Program:
- Neuroscience
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- February 25, 2008
- Committee Members:
- Gong Chen, Thesis Advisor/Co-Advisor
Andrew Ewing, Thesis Advisor/Co-Advisor - Keywords:
- epilepsy
THIP
tonic inhibition
CTZ
GABA - Abstract:
- The majority of the inhibition in the brain is mediated by GABA-A receptors. Synaptic GABA-A receptors enforce a strong, activity dependent inhibition, known as phasic inhibition. Extrasynaptic GABA-A receptors maintain a comparatively mild and continuous inhibition known as tonic inhibition. Previous work from the Chen laboratory has shown that chronic treatment with cyclothiazide (CTZ) induces epileptiform activity in mature rat hippocampal cultures, which is accompanied by a selective downregulation of extrasynaptic GABA-A receptors (Qi et al., 2006). The purpose of the present study was to determine whether downregulation of tonic inhibition mediated by extrasynaptic GABA-A receptors is causally linked to the formation and/or maintenance of epileptiform activity. A selective extrasynaptic GABA-A receptor agonist, THIP (Gaboxadol), was used at low concentration to study its effect on CTZ induced epileptiform activity. Chronic treatment of hippocampal cultures with CTZ induces epileptiform activity in about 80% of neurons. After simultaneous chronic treatment of cultures with CTZ and THIP, the percentage of neurons showing epileptiform activity was reduced to about 40%. Additionally, spontaneous epileptiform activity established in old hippocampal cultures was also studied and chronic treatment with THIP nearly abolished it. Acute THIP treatment reduced spontaneous epileptiform activity significantly. Besides reducing firing strength, chronic activation of tonic currents also reduces the frequency of synchronous network bursts, which may otherwise impede hippocampal learning. Our data suggests that tonic inhibition contributes towards maintenance of cellular epileptiform activity and drugs that activate it could be potential modulators of pathological hyperactive states like epilepsy as well.