Role of Delta Subunit-Containing GABAA Receptors in Hippocampus Tonic Inhibition and Epileptogenesis within Transgenic Mouse Models

Abstract

Epilepsy is associated with marked alterations in the structure and function of GABAA receptors in the hippocampus, a key structure for the genesis of epilepsy. Two types of inhibition are mediated via distinct GABAA receptors. Phasic inhibition results from the synaptic γ2-containing receptors, whereas tonic inhibition is primarily mediated by the continuous activation of δ-containing, extrasynaptic receptors by ambient GABA present in the extracellular fluid. The δ-subunit receptors exhibit greater sensitivity to neurosteroid potentiation through positive allosteric modulation. The abundance of δ-subunit and the extent of tonic inhibition are altered by physiological and pathological neuroendocrine conditions. However, the precise functional impact of δ-subunit on inhibition in the hippocampus and epileptogenesis remain poorly understood.

The main objective of this dissertation research was to understand the role of δ-subunit-containing GABAA receptors in the hippocampus dentate gyrus in mediation of tonic inhibition and epileptogenesis using a combination of electrophysiological, behavioral, and pharamcological techniques. We sought to understand the contribution of δ subunit to GABAergic inhibition and network excitability. We incorporated a perimenstrual model of catamenial epilepsy in which female mice experience acute neurosteroid withdrawal. The correlates of receptor plasticity and function were then examined. Furthermore, the structure-activity relationship of neurosteroids at extrasynaptic GABAA receptors was investigated in conducting the tonic inhibition. Alterations to hippocampus epileptogenesis of the δ-subunit knockout mouse as a model for hyperexcitability and susceptibility to seizures was also explored. Overall, these studies reveal a unique and novel role for δ-subunit-containing GABAA receptors as key modulators of tonic inhibition and excitability in the brain. These extrasynaptic receptors may represent new therapeutic targets for the control of epileptic conditions.