Experimental status epilepticus alters γ‐aminobutyric acid type A receptor function in CA1 pyramidal neurons

Abstract

There is a reduction of γ-aminobutyric acid (GABA)-mediated inhibition in the CA1 pyramidal region of the hippocampus during status epilepticus (SE). The cellular basis of this loss of GABAmediated inhibition is not known. This study tested the possibility that GABA type A (GABA A ) receptor function in CA1 pyramidal neurons was reduced or blocked during SE, at least in part by postsynaptic cellular mechanisms. GABA A , receptor currents (I GABA ) were studied by whole-cell patch-clamp techniques in CA1 pyramidal neurons acutely dissociated from rats undergoing lithium/pilocarpine-induced limbic status epilepticus (SE neurons) and from naive rats (naive neurons). SE neurons had more depolarized resting membrane potential (−17.3 mV) compared with naive neurons (−56 mV). I GABA was absent in 47% of SE neurons and reduced in 55% of the remainder, compared with naive neurons. The reduction in I GABA in SE neurons resulted from a combination of factors, including reduced potency and reduced efficacy of GABA in activating chloride channels, and diminished driving force for the GABA-induced chloride currents once activated. These postsynaptic cellular mechanisms resulted in a net reduction or loss in GABAmediated inhibition and may explain previous in vivo findings reporting a loss of inhibition in hippocampus during limbic SE.Convulsive status epilepticus (SE) is a medical emergency that can result in brain damage or even death. While death following treated SE is usually a consequence of the underlying cause of SE, mortality is also related to seizure duration [1]. Neurologic morbidity including neuropsychological dysfunction [2], increased risk for subsequent seizures, and a low incidence of spontaneous remission of underlying epilepsy is associated with SE [2]. Improvement in prognosis of patients with SE will result from a better understanding of the pathophysiology of SE. A key to understanding the pathophysiology of SE was the development and validation of various animal models of this disorder. One such model initially described by Honchar and colleagues [3] was based on cholinergic stimulation of the brain by sequential administration of lithium and pilocarpine. Treiman and associates [4] found that a predictable sequence of electroencephalographic (EEG) changes that occurred during the course of human convulsive SE was replicated in lithium/pilocarpine-induced SE in rats [5]. In addition, the profile of efficacy of anticonvulsants in an animal model of SE was similar to that in human convulsive SE [6].There is a critical role for loss of γ-aminobutyric acid type A (GABA A )-mediated inhibition in the CA1 region of the hippocampus in partial onset SE in experimental animals [7]. SE induced by lithium and pilocarpine resulted in reduction of the number of GABA A receptors (GABARs) in the rat forebrain; and injection of a combination of lithium and pilocarpine resulted in reduction of GABA A -mediated inhibition in the CA1 region of the hippocampus

Ketamine controls prolonged status epilepticus

“…Development of resistance to phenobarbital during status epilepticus supports the hypothesis that GABA A receptormediated inhibition diminishes during status epilepticus (Kapur, 1999;Kapur and Coulter, 1995;Kapur and Macdonald, 1997). Despite differences in the mechanism of action of benzodiazepines and barbiturates on GABA A receptors (Macdonald and Olsen, 1994), development of resistance to both drugs suggests that prolonged seizures alter the structure and/or function of GABA A receptors.…”

Rundown of GABA type A receptors is a dysfunction associated with human drug-resistant mesial temporal lobe epilepsy

“…For example, in animal models, it has been postulated that the decreased inhibition during status epilepticus is due, at least partly, to alterations of postsynaptic GABA A -receptors caused by the seizures (20)(21)(22). In humans, many forms of epilepsies and epileptic syndromes are susceptible to antiepileptic medications that affect GABAergic function.…”

Rapid Seizure-Induced Reduction of Benzodiazepine and Zn2+Sensitivity of Hippocampal Dentate Granule Cell GABAAReceptors

“…Several possible mechanisms can be hypothesized to explain the loss of diazepam effectiveness in the treatment of prolonged seizures of status epilepticus; seizures may become more intense, there may be enhanced excitatory transmission, or there may be altered inhibition. Past studies indicate that the hippocampus is involved in the generation of status epilepticus (Lothman et al, 1991;VanLandingham and Lothman, 1991;Kapur and Macdonald, 1996), and hippocampal GABAergic inhibition is altered during status epilepticus (Kapur and Lothman, 1989;Kapur and Coulter, 1995). These studies suggested that refractoriness of seizures to diazepam may result from altered GABAR function in the hippocampus.…”

“…Prolonged hippocampal seizures reduce GABAR inhibition (Kapur et al, , 1994Sloviter, 1991), and this reduction of inhibition is correlated with the development of status epilepticus (Kapur and Lothman, 1989). The cellular mechanisms underlying this loss of GABAergic inhibition during status epilepticus seem to be postsynaptic, including reduced potency and efficacy of GABA in activating chloride channels and diminished driving force for the GABAR currents (Kapur and Coulter, 1995). Thus one hypothesis explaining the self-sustaining nature of status epilepticus is that prolonged seizures produce a progressive reduction of GABAR inhibition in the hippocampus that leads to the development of status epilepticus.…”