Acute cellular alterations in the hippocampus after status epilepticus

The critical, fundamental mechanisms that determine the emergence of status epilepticus from a single seizure and the prolonged duration of status epi lepticus are uncertain. However, several general concepts of the pathophysi ology of status epilepticus have emerged: (a) the hippocampus is consistent ly activated during status epilepticus; (b) loss of GABA-mediated inhibitor y synaptic transmission in the hippocampus is critical for emergence of sta tus epilepticus; and, finally (c) glutamatergic excitatory synaptic transmi ssion is important in sustaining status epilepticus. This review focuses on the alteration of GABAergic inhibition in the hippocampus that occurs duri ng the prolonged seizures of status epilepticus. If reduction in GABAergic inhibition leads to development of status epi lepticus, enhancement of GABA ergic inhibition would be expected to interrupt status epilepticus. Benzodi azepines and barbiturates are both used in the treatment of status epilepti cus and both drugs enhance GABA(A) receptor-mediated inhibition. However, p atients often become refractory to benzodiazepines when seizures are prolon ged, and barbiturates are often then used for these refractory cases of sta tus epilepticus. Recent evidence suggests the presence of multiple GABA(A) receptor isoforms in the hippocampus with different sensitivity to benzodia zepines but similar sensitivity to barbiturates, thus explaining why the tw o drug classes might have different clinical effects. In addition, rapid fu nctional plasticity of GABA(A) receptors has been demonstrated to occur dur ing status epilepticus in rats. During status epilepticus, there was a subs tantial reduction of diazepam potency for termination of the seizures. The loss of sensitivity of the animals to diazepam during status epilepticus wa s accompanied by an alteration in the functional properties of hippocampal dentate granule cell GABA(A) receptors. Dentate granule cell GABA(A) recept or currents from rats undergoing status epilepticus had reduced sensitivity to diazepam and zinc but normal sensitivity to GABA and pentobarbital. The refore, the prolonged seizures of status epilepticus rapidly altered the fu nctional properties of hippocampal dentate granule cell GABA(A) receptors, possibly explaining why benzodiazepines and barbiturates may not be equally effective during treatment of the prolonged seizures of status epilepticus . A comprehensive understanding of the cellular and molecular events leadin g to the development, maintenance, and cytotoxicity of status epilepticus s hould permit development of more effective treatment strategies and reducti on in the mortality and morbidity of status epilepticus.