GABA and Its Receptors in Epilepsy

Abstract

γ-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain. It acts through 2 classes of receptors, GABA_A receptors that are ligand-operated on channels and the G-protein-coupled metabotropic GABA_B receptors. Impairment of GABAergic transmission by genetic mutations or application of GABA receptor antagonists induces epileptic seizures, whereas drugs augmenting GABAergic transmission are used for antiepileptic therapy. In animal epilepsy models and in tissue from patients with temporal lobe epilepsy, loss in subsets of hippocampal GABA neurons is observed. On the other hand, electrophysiological and neurochemical studies indicate a compensatory increase in GABAergic transmission at certain synapses. Also, at the level of the GABA_A receptor, neurodegeneration-induced loss in receptors is accompanied by markedly altered expression of receptor subunits in the dentate gyrus and other parts of the hippocampal formation, indicating altered physiology and pharmacology of GABA_A receptors. Such mechanisms may be highly relevant for seizure induction, augmentation of endogenous protective mechanisms, and resistance to antiepileptic drug therapy. Other studies suggest a role of GABA_B receptors in absence seizures. Presynaptic GABA_B receptors suppress neurotransmitter release. Depending on whether this action is exerted in GABAergic or glutamatergic neurons, there may be anticonvulsant or proconvulsant actions.

γ—aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain.¹ It acts through 2 classes of receptors, GABA_A receptors that are ligand-operated ion channels and the G-protein-coupled metabotropic GABA_B receptors (for review see ref. 2). GABAergic neurons are ubiquitously distributed and encompass a fundamental role in processing and integration of all neuronal functions. It is therefore not surprising that blockade of the fast inhibitory GABA_A receptors by bicuculline, pentylenetetrazol or picrotoxin causes severe motor seizures in experimental animals.^3,4 It has therefore been suggested that dysfunction of the GABAergic system may have a fundamental role in the propagation of acute seizures and in the manifestation of epilepsy syndromes. Indeed, mutant mice lacking the enzyme glutamate decarboxylase (GAD) or certain subunits of GABA_A receptors are prone to spontaneous epileptic seizures.^5–7 In the same way, patients with auto-antibodies to the enzyme GAD-67 suffer from the so called Stiff-man-syndrome, and often develop also epilepsy.^8,9

One of the most serious and frequent epilepsy syndromes is temporal lobe epilepsy (TLE). It is initiated by prolonged febrile seizures or status epilepticus, and takes years or even more than a decade until it is manifested.^10,11 In the clinic, TLE is difficult to treat, and patients frequently become resistant to drug therapy.¹² Repeated and prolonged seizures may also contribute to the severe neuronal damage observed in the temporal lobe, notably in the hippocampus, entorhinal cortex, amygdala and other brain areas.^13,14 One of the most typical features is the severe loss of principal neurons in the hippocampus proper, notably in sectors CA1 and CM3, whereas granule cells of the dentate gyrus, and pyramidal neurons of the sector CA2 and the subiculum, are relatively spared.^10,15

Because of its clinical relevance and the feature that TLE develops over a prolonged “silent” period, considerable effort has been made through the past decades to investigate its pathophysiology. Animal models mimicking different aspects of TLE, like the induction by severe status epilepticus, subsequent epileptogenesis, and manifestation of spontaneous seizure activity, have been developed.^16–19 These models, and hippocampal tissue specimens obtained at surgery from patients with drug-resistant TLE, became valuable objects for studying the pathophysiology of the disease (see refs. 20–23).