Date of Award

8-9-2014

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

David D. Mott

Abstract

Status epilepticus (SE) is a life-threatening neurologic emergency occurring when the brain is in an unrelenting state of seizure activity. Approximately 40% of people who encounter a single event of SE go on to develop epilepsy, characterized by spontaneously occurring seizures. While the exact mechanisms underlying seizure origin are not understood, at a fundamental level seizures initiate due to an imbalance between inhibitory and excitatory neurotransmission. We explored the impact of SE and the development of epilepsy on GABAA receptor mediated inhibitory neurotransmission and kainate receptor (KAR) mediated excitatory neurotransmission.

Stiripentol (STP), a positive allosteric modulator of the GABAA receptor, was found to terminate both brief and prolonged SE with the development of less pharmacoresistance than is observed with the benzodiazepine (BZD), diazepam (DZP). In addition STP, but not DZP, retained its ability to potentiate both phasic and tonic GABAergic transmission post-SE. These findings are supported by previous studies demonstrating that the actions of STP do not require the BZD-sensitive γ2-containing GABAARs which are internalized during prolonged SE. These data demonstrate that prolonged SE significantly impacts the pharmacological profile of GABAA receptors and potential therapeutics.

x

KARs densely populate the hippocampal mossy fiber – CA3 pathway where they mediate a portion of excitatory neurotransmission. Significant alterations in KAR subunit expression in the dentate gyrus and CA3 regions were observed in animals at 5, 60 and 200 day post-SE. These changes were dynamic and region specific. In agreement with observed alterations in subunit expression, KAR-mediated neurotransmission was significantly reduced at mossy fiber – CA3 synapses in epileptic animals. In addition, synaptic integration by KARs during repetitive stimulation was also significantly impaired. These data demonstrate that SE significantly impacts KAR-mediated excitatory neurotransmission.

Together these studies provide new insight into the impact of SE and the development of epilepsy on both GABAA and KAR-mediated neurotransmission. The observed alterations following SE may contribute to the generation of seizures or may be compensatory mechanisms to reduce the likelihood of seizure initiation. Furthermore, these findings demonstrate the dramatic alterations observed in the diseased brain and emphasize the importance of acknowledging these differences for the development of effective therapeutics.

Rights

© 2014, Denise K Grosenbaugh

Download

Share

COinS