Electrical excitability of cortical neurons is regulated, in large part, by excitatory glutamatergic and inhibitory GABAergic input. Dysregulation of this system appears to underlie the initiation and propagation of seizures. With prolonged seizures, there is a change in GABAA receptor function. At an organismic level, this may be associated with benzodiazepine insensitivity, requiring high dose barbiturates to abort seizures. At a cellular level there is attenuation of both benzodiazepine and zinc modulation of GABAA receptors on isolated dentate granule cells. Although CA1 hippocampal neurons become relatively GABA insensitive, no such change in GABA pharmacology at GABAA receptors on granule cells has been seen. However, the effect of seizures on the fast components of GABAA receptor activation/deactivation/desensitization has not been explored. Since synaptically-released GABA is thought to be present in the synaptic cleft for only 1-2 ms, these fast components of GABAA receptor activation may profoundly alter the shape of GABAergic post-synaptic potentials. These studies will investigate the changes in GABAA receptor function on isolated dentate granule cells using a rapid drug delivery system following prolonged seizures induced in rats with Lithium/pilocarpine. Firstly, GABA concentration response relationships will be determined. Next, the rapid components of GABAA receptor kinetics will be determined using a cell-attached voltage clamp technique with rapid drug delivery. Furthermore, single channel kinetics will also be measured in cells from control and animals which have undergone seizures. Finally, the effect of seizures on GABAA receptor allosteric modulators will be determined. In addition to being intrinsically interesting and potentially clinically useful, the pattern of these effects may provide important clues as to whether the changes in GABAA receptor function are due to a rearrangement of the subunits making up those receptors. These studies seek to elucidate the changes in GABAA receptor function seen after prolonged seizures. This may help further our understanding of seizure initiation/abortion as well as normal GABAergic synaptic transmission. ? ?
