While most partial and generalized seizures are relatively brief in duration, during some seizures, early termination fails and a prolonged epileptic state occurs that has been termed status epilepticus. Status epilepticus is relatively common, has a high morbidity and mortality and is a medical emergency requiring immediate treatment. Spontaneous seizure termination may involve activation of gamma-aminobutyric acid (GABA) receptor (GABAR)-mediated inhibition. If the GABAergic inhibition fails to terminate the seizure, a progressive reduction of GABAR-mediated inhibition develops that, when severe enough, results in a prolonged seizure. Status epilepticus in humans is treated acutely with benzodiazepines as well as barbiturates, which enhance GABAR-mediated inhibition. However, benzodiazepines are often efficacious early but not late in status epilepticus. We have shown that properties of dentate granule cell GABAR are altered during prolonged seizures in rats, with a reduction in benzodiazepine and zinc sensitivity without a change in GABA or pentobarbital sensitivity. These observations suggest that GABAR function changes during prolonged seizures, extending seizure duration and producing refractoriness to benzodiazepine treatment. Development of an understanding of this seizure-induced receptor plasticity would enhance understanding of spontaneous seizure termination and permit development of new treatment strategies for status epilepticus. The hypothesis to be tested is that during prolonged seizures, hippocampal dentate granule cell GABAR pharmacological and biophysical properties change due either to a change in receptor subtype composition or to receptor phosphorylation.
The specific aims are to determine the : 1) dependence on seizure duration of development of insensitivity to benzodiazepines, 2) time course of development of decreased sensitivity of granule cell GABAR currents to diazepam and zinc, 3) sensitivity of granule cell GABAR currents GABAR modulators following prolonged seizures, 4) transient and steady state kinetic properties of granule cell GABAR single channel currents following prolonged seizures, 5) rate of recovery of regulation by diazepam and zinc of granule cell GABAR current following prolonged seizures, 6) rate of recovery of regulation by allosteric regulators of granule cell GABAR current following prolonged seizures, 7) dependence on PKA of recovery of granule cell GABAR current following prolonged seizures, 8) dependence on other kinases of recovery of granule cell GABAR current following prolonged seizures and 9) regulation of benzodiazepine, zinc and other allosteric regulator sensitivity of GABARs by phosphorylation.
