Carver, Chase M (2015-05). Role of Delta Subunit-Containing GABAA Receptors in Hippocampus Tonic Inhibition and Epileptogenesis within Transgenic Mouse Models. Doctoral Dissertation. Thesis uri icon

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 ?2-containing receptors, whereas tonic inhibition is primarily mediated by the continuous activation of ?-containing, extrasynaptic receptors by ambient GABA present in the extracellular fluid. The ?-subunit receptors exhibit greater sensitivity to neurosteroid potentiation through positive allosteric modulation. The abundance of ?-subunit and the extent of tonic inhibition are altered by physiological and pathological neuroendocrine conditions. However, the precise functional impact of ?-subunit on inhibition in the hippocampus and epileptogenesis remain poorly understood. The main objective of this dissertation research was to understand the role of ?-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 ? 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 ?-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 ?-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.
  • 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 ?2-containing receptors, whereas tonic inhibition is primarily mediated by the continuous activation of ?-containing, extrasynaptic receptors by ambient GABA present in the extracellular fluid. The ?-subunit receptors exhibit greater sensitivity to neurosteroid potentiation through positive allosteric modulation. The abundance of ?-subunit and the extent of tonic inhibition are altered by physiological and pathological neuroendocrine conditions. However, the precise functional impact of ?-subunit on inhibition in the hippocampus and epileptogenesis remain poorly understood.

    The main objective of this dissertation research was to understand the role of ?-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 ? 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 ?-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 ?-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.

publication date

  • May 2015