GABAA receptors (GABAARs) that contain the ( subunit play an important role in regulating the excitability of the hippocampus through tonic inhibition and are quite sensitive to modulation by neurosteroids and ethanol. Thus alterations in these receptors could play a critical role in epilepsy. In an animal model of recurrent seizures, alterations in GABAARs include a decrease in ( subunit expression in granule cells of the dentate gyrus and an intriguing increase in ( subunit expression in interneurons. Both changes could contribute to increased seizure susceptibility. The broad goal of this project is to obtain new information about the location and function of the ( subunit of the GABAAR in hippocampal interneurons in normal and epileptic animals. A combination of light and electron microscopic immunohistochemical methods will be used to identify altered expression and localization of the ( subunit, and functional correlates will be determined with electrophysiological methods in a mouse model of epilepsy. The First Specific Aim is to identify and characterize the subgroups of GABA neurons in the hippocampus that express the ( subunit as well as those that may lack substantial ( subunit expression. The Second Specific Aim is to test the hypothesis that the subcellular locations the ( and a1 subunits are altered in interneurons of epileptic animals. Electron microscopy and immunogold labeling will be used to determine if changes occur at synaptic or nonsynaptic locations on dentate interneurons in pilocarpine-treated animals. The Third Specific Aim is to test the hypothesis that increased expression of the ( subunit in interneurons increases tonic inhibition in these neurons and reduces their responsiveness within the hippocampal circuit of epileptic mice. A novel optical voltage sensor method will be used for reporting neuronal activity in a subset of these studies. The Fourth Specific Aim will test the hypothesis that interneurons with increased ( subunit expression in epileptic animals will be less readily activated in vivo in response to seizure activity than similar interneurons in controls. The studies could identify new types of GABAAR subunit plasticity in epilepsy and determine the functional consequences of ( subunit alterations in seizure disorders.
The studies will provide new information about the location and function of GABA receptors that help control excitability of the brain and are thus important for preventing seizures. Identifying alterations in these receptors in an epilepsy model could provide new insights into the changes that lead to epilepsy and also suggest new approaches for the treatment of seizure disorders.
| Wyeth, M S; Zhang, N; Houser, C R (2012) Increased cholecystokinin labeling in the hippocampus of a mouse model of epilepsy maps to spines and glutamatergic terminals. Neuroscience 202:371-83 |
| Houser, Carolyn R; Zhang, Nianhui; Peng, Zechun et al. (2012) Neuroanatomical clues to altered neuronal activity in epilepsy: from ultrastructure to signaling pathways of dentate granule cells. Epilepsia 53 Suppl 1:67-77 |
