Chapter category: Neuroscience
GABA and its Receptors in Epilepsy
Recent Advances in Epilepsy Research
Edited by: Devin K. Binder and Helen E. ScharfmanISBN: 0-306-47860-9
» Get more information about this book at landesbioscience.com «
Chapter authors:
Günther Sperk, Sabine Furtinger, Christoph Schwarzer and Susanne Pirker
g-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain. It acts through 2 classes of receptors, GABAA receptors that are ligand-operated ion channels and the G-protein-coupled metabotropic GABAB receptors. Impairment of GABAergic transmission by genetic mutations or application of GABA receptor antagonists induce 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 GABAA 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 GABAA 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 GABAB receptors in absence seizures. Presynaptic GABAB receptors suppress neurotransmitter release. Depending on whether this action is exerted in GABAergic or glutamatergic neurons, there may be anticonvulsant or proconvulsant actions. g-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain.1 It acts through 2 classes of receptors, GABAA receptors that are ligand-operated ion channels and the G-protein-coupled metabotropic GABAB 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 GABAA receptors by bicuculline, pentylentetrazole or picrotoxin causes severe motor seizures in experimental animals.3,4 It has therefore been suggested that dysfunction of the GABA-ergic 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 GABAA 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 CA3, 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).
Additional chapters from this book:
The Tetanus Toxin Model of Chronic Epilepsy
Timothy A. Benke and John Swann
In experimental models of epilepsy, single and recurrent seizures are often used in an attempt to determine the effects of the seizures themselves on mammalian brain function. These models attempt t...
Functional Implications of Seizure-Induced Neurogenesis
Helen E. Scharfman
The neurobiological doctrine governing the concept of neurogenesis has undergone a revolution in the past few years. What was once considered dubious is now well accepted: new neurons are born in th...
Malformations of Cortical Development: Molecular Pathogenesis and Experimental Strategies
Peter B. Crino
Malformations of cortical development (MCD) are developmental brain lesions characterized by abnormal formation of the cerebral cortex and a high clinical association with epilepsy in infants, child...
Using the Immune System to Target Epilepsy
Deborah Young and Matthew J. During
The sudden and transient disruption from normal brain function by the disordered, synchronous and rhythmic firing of populations of neurons or seizures is the common feature of a diverse collection ...
Functional Role of Proinflammatory and Anti-Inflammatory Cytokines in Seizures
Annamaria Vezzani, Daniela Moneta, Cristina Richichi, Carlo Perego and Maria G. De Simoni
Recent evidence has shown that proinflammatory and anti-inflammatory molecules are synthesized during epileptic activity in glial cells in CNS regions where seizures initiate and spread. These molec...
Gap Junctions, Fast Oscillations and the Initiation of Seizures
Roger D. Traub, Hillary Michelson-Law, Andrea E.J. Bibbig, Eberhard H. Buhl and Miles A. Whittington
In this chapter, we shall review evidence that gap junctions can contribute to epileptogenesis in the hippocampus and cortex—but not just any gap junctions. Rather, we shall argue for a role for a n...
Role of the Depolarizing GABA Response in Epilepsy
Kevin J. Staley
The term “seizure” underscores two fundamental characteristics of epileptic phenomena: they are sudden and unexpected deviations from the normal function of the nervous system. Thus 2 important crit...
Role of the GABA Transporter in Epilepsy
George B. Richerson and Yuanming Wu
The GABA transporter plays a well-established role in reuptake of GABA after synaptic release. The anticonvulsant effect of tiagabine appears to result largely from blocking this reuptake. However, ...
Plasticity Mechanisms Underlying mGluR-Induced Epileptogenesis
Robert K.S. Wong, Shih-Chieh Chuang and Riccardo Bianchi
Transient application of group I metabotropic glutamate receptor (mGluR) agonists to hippocampal slices produces ictal-like discharges that persist for hours after the removal of the agonist. This e...
Vascular Endothelial Growth Factor (VEGF) in Seizures: A Double-Edged Sword
Susan D. Croll, Jeffrey H. Goodman and Helen E. Scharfman
Vascular endothelial growth factor (VEGF) is a vascular growth factor which induces angiogenesis (the development of new blood vessels), vascular permeability, and inflammation. In brain, receptors ...
The Role of BDNF in Epilepsy and Other Diseases of the Mature Nervous System
Devin K. Binder
The neurotrophin brain-derived neurotrophic factor (BDNF) is ubiquitous in the central nervous system (CNS) throughout life. In addition to trophic effects on target neurons, BDNF appears to be part...
Genetic Approaches to Studying Mouse Models of Human Seizure Disorders
Yan Yang and Wayne N. Frankel
Epilepsy, characterized by recurrent spontaneous seizures resulting from abnormal, synchronized discharges of neurons in the brain, is one of the most common neurological problems afflicting humans....
Cortical Dysplasia and Epilepsy: Animal Models
Philip A. Schwartzkroin, Steven N. Roper and H. Jurgen Wenzel
Cortical dysplasia syndromes – those conditions of abnormal brain structure/organiza- tion that arise during aberrant brain development – frequently involve epileptic sei- zures. Neuropathological...
Brain Stimulation as a Therapy for Epilepsy
Jeffrey H. Goodman
The failure of current antiepileptic therapies to adequately treat a significant number of epileptic patients highlights the need for the development of new treatments for the disorder. A new st...
Integrins, Synaptic Plasticity and Epileptogenesis
Christine M. Gall and Gary Lynch
A number of processes are thought to contribute to the development of epilepsy inclu- ding enduring increases in excitatory synaptic transmission, changes in GABAergic inhi- bition, neuronal cell ...
GABA and its Receptors in Epilepsy
Günther Sperk, Sabine Furtinger, Christoph Schwarzer and Susanne Pirker
g-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain. It acts through 2 classes of receptors, GABAA receptors that are ligand-operated ion channels and the G-...
Febrile Seizures and Mechanisms of Epileptogenesis: Insights from an Animal Model
Roland A. Bender, Celine Dubé and Tallie Z. Baram
Temporal lobe epilepsy (TLE) is the most prevalent type of human epilepsy, yet the causes for its development, and the processes involved, are not known. Most individuals with TLE do not have a family...
