bluuebunny/crossref_metadata_2025_split huggingface dataset:
GABAB Receptor and Absence Epilepsy
Authors: Han Hua A. , Cortez Miguel A. , Snead O. Carter 
Published: May 2013

Abstract
GABABR-mediated mechanisms have been known for many years to be involved in the genesis and propagation of both TASs126–129 and AASs,78,84 as well as in the associated cognitive impairments.54,79 Moreover, the data reviewed in this chapter indicate that TAS and AAS share the same pharmacological profile, because they share common thalamic circuitry perturbations, notably nRT involvement. However, TAS and AAS phenotypes differ in seizure severity, SWD characteristics, and impairment in learning abilities, mainly because they differ in the other parts of the circuitry involved. In TAS, cognition is not affected because the SWD is constrained within thalamocortical circuits and does not involve limbic circuits. In AAS, on the other hand, cognition is impaired because of the SWD involvement of limbic circuitry that is recruited through cortico-thalamo-hippocampal pathways,130 hence the difference in seizure semiology and cognitive involvement. Because of the demonstrated efficacy of GABABR antagonists in preventing SWDs, the potential of GABABR antagonists as powerful antiabsence drugs has been long proposed,61 yet clinical trials of GABABR are lacking both in TAS and AAS. Frequent refractory seizures and severe impairment in cognition represent the most disabling aspects of pediatric epilepsy and are the major contributors to the burden of illness in children affected by epilepsy.131 Because of data suggesting that atypical absence seizures are independent of their comorbid cognitive deficits, yet both are GABABR dependent,79 there is a clinical imperative to initiate clinical trials of a GABABR antagonist in the AASs observed in Lennox-Gastaut syndrome.119,120
Computer Modeling of Epilepsy
Authors: Case Marianne J. , Morgan Robert J. , Schneider Calvin J. , Soltesz Ivan 
Published: May 2013

Abstract
There are 50 million people worldwide afflicted with epilepsy, and for roughly 15 million of them, existing epilepsy treatments are not sufficient.1 Such stark facts spur clinicians and researchers to consider dramatically different approaches to treatment, such as an implantable device that could characterize electrical activity in real time, immediately detect when the brain reaches a preictal state, and apply a counteracting current waveform, averting the seizure before it starts (see the next section),2 or an individualized, detailed model of the patient's brain—complete with patient-specific details such as genetic mutations or head trauma—to which doctors could administer virtual drugs to determine the best treatment regimen for that person. Such a tool would complement existing therapies by reducing the likelihood of patients being subjected to treatments to which they are unresponsive.
Traumatic Brain Injury and Posttraumatic Epilepsy
Authors: Prince David A. , Parada Isabel , Graber Kevin D. 
Published: May 2013

Abstract
The epidemiology of posttraumatic epilepsy (PTE) has been extensively analyzed and reviewed in a number of studies of both civilian and military brain injuries1,2 (reviewed in ref. 3). Several conclusions from this research are relevant to considerations of the potential mechanisms and prophylaxis of PTE. Results clearly show that the incidence of PTE is related to the severity of injury, and is therefore significantly higher in the military during wartime than in the civilian population, ranging up to 53% with penetrating wounds1,2 (reviewed in ref. 3). Both the increased incidence at older ages and the potential development of PTE by the large number of individuals who have survived severe concussive injury during recent conflicts suggest that the size of the affected population will increase in coming years, emphasizing the need for understanding the underlying pathophysiological processes and the development of prophylactic strategies.4,5 Although initial seizures in those who develop epilepsy most commonly have a focal origin in neocortex, both partial neocortical and temporal lobe epilepsy can follow traumatic brain injury (TBI) in humans.6 One remarkable feature of PTE is the variable, often very prolonged latency from injury to epilepsy, which can range from weeks to years.1,2,6 This provides a possible window for prophylactic intervention once more information regarding the underlying pathophysiological processes and strategies for modifying them is available. However, the long latency also represents a potential therapeutic problem, particularly in the absence of reliable biomarkers of epileptogenesis in progress. This chapter will focus on examples of aberrant excitatory and inhibitory processes in injured epileptogenic cortex and potential approaches to prevention of epileptogenesis that are focused on these pathophysiological mechanisms. Some of the challenges for the development of prophylactic therapies are also discussed. Readers are referred to a number of reviews and papers published very recently that deal with various aspects of the basic mechanisms, pathogenesis, and potential prophylaxis of PTE and complement the areas covered in this chapter.6–18
Programmed Necrosis after Status Epilepticus
Authors: Niquet Jerome , Lopez-Meraz Maria-Leonor , Wasterlain Claude G. 
Published: May 2013

Abstract
In this review, we will discuss the most recent advances in the field of neuronal injury following epileptic seizures, with an emphasis on the mechanism of neuronal necrosis. The ultrastructure of cell death and the ubiquity of endogenous cell death programs were first described in the 1970s, and the two main categories of cell death, apoptosis and necrosis, were originally defined according to morphological criteria.1 The role of glutamate and its analogues in excitotoxic cell death, and the concept of excitotoxicity—including its role in seizures—derived from the pioneering studies of John Olney and his disciples.2–5 Multiple cell death factors and cell death programs have been identified in developmental and disease-induced neuronal apoptosis,6–8 and there is mounting clinical and experimental evidence of their contribution to seizure-induced neuronal injury.9–16 Because these death factors were originally identified in classic apoptosis, any form of cell death in which they are expressed is often called apoptotic, even if its morphology suggests necrosis. This has caused considerable confusion in the literature and should be discouraged.17–20 In this chapter, we will discuss the involvement of cell death factors in morphologically defined necrosis, the main mode of status epilepticus (SE)-induced cell death in the adult and even in the developing brain. We find that necrosis is frequently an active form of neuronal death, requiring the expression or activation of some of the same cell death factors usually identified with apoptosis. While this finding raises the hope that targeting common cell death pathways might have therapeutic benefits for both necrosis and apoptosis, the multiplicity and redundancy of cell death pathways for both modes of neuronal death also raise formidable problems when we consider the potential therapeutic applications of these mechanisms.
Kainate and Temporal Lobe Epilepsies
Authors: Ben-Ari Yehezkel 
Published: May 2013

Abstract
Understanding the role of kainate signals in modulating ongoing neuronal and network-driven patterns of activity has enormously benefited from the parallel investigation of pathological and normal tissue. The past three decades have shown how kainate generates seizures and how neurons susceptible to kainate are also the ones that use it for ongoing biological functions. Clearly, the system relies on the unique capacity of kainate signals to generate biologically relevant patterns by activating a wide range of cellular mechanisms that converge to enhance neuronal excitability. Theses systems, however, “live dangerously,” since insults can transform these activities into severe life-long neurological disorders. It is this link that we must better understand if we want to efficiently block pharmacoresistant TLE.
Abnormal Dentate Gyrus Network Circuitry in Temporal Lobe Epilepsy
Authors: Sloviter Robert S. , Bumanglag Argyle V. , Schwarcz Robert , Frotscher Michael 
Published: May 2013

Abstract
The mechanisms that cause acquired temporal lobe epilepsy are unknown. Suspected mechanisms include neuron loss, synaptic reorganization, and granule cell dispersion, but determining which abnormalities mediate epileptogenesis has been problematic because the most frequently used chemoconvulsant-based animal models exhibit extreme variability and minimal evidence of hippocampal epileptogenesis. Continuous monitoring of behavior and granule cell layer activity in awake rats after hippocampal injury caused by stimulation-induced status epilepticus has now shown that granule cells generate spontaneous field depolarizations, population spikes, and epileptiform discharges in the first days post-injury, prior to each generalized behavioral seizure. Thus, injury-associated hippocampal epileptogenesis is coincident with initial neuron loss, not delayed secondary processes. We hypothesize that neuron loss in the entorhinal cortex disrupts the functional separation of Layer II “grid cells,” causing abnormal synchronous discharges that invade the dentate gyrus. This, in turn, produces population spikes and epileptiform discharges in granule cells disinhibited by injury-induced hilar neuron loss. Long delays between injury and generalized behavioral seizures, when they occur, may primarily involve a “kindling” process in which initially focal (subclinical) discharges gradually increase in duration and cause clinical seizures. Neuroprotection in the immediate post-injury period, and prolonged anti-kindling therapy, might be the most effective anti-epileptic strategy.
Seizure-Induced Formation of Basal Dendrites on Granule Cells of the Rodent Dentate Gyrus
Authors: Ribak Charles E. , Shapiro Lee A. , Yan Xiao-Xin , Dashtipour Khashayar , Nadler J. Victor , Obenaus Andre , Spigelman Igor , Buckmaster Paul S. 
Published: May 2013

Abstract
Granule cells of the normal adult rodent dentate gyrus generally have the typical morphology of bipolar cells. Their apical dendrites arise from one pole and arborize into the molecular layer, while the axon originates from the base of the granule cell body and extends into the hilus subjacent to the granule cell layer.1 Two exceptions to this rule have been observed. Sometimes recurrent basal dendrites arise from the base of granule cell bodies and then curve back through the granule cell layer in the direction of the molecular layer, where they join apical dendrites.2–4 Despite this unusual origination, dendrites of dentate granule cells in rodents arborize exclusively in the molecular layer. The other exception is the rare instance of an axon originating from the granule cell's apical dendrite or the apical pole of its cell body.4 In this instance, the axon descends into the hilus without giving rise to collaterals. Both of these morphologies suggest that rat granule cells are more heterogeneous than was previously indicated. Dentate granule cells from humans and nonhuman primates differ from granule cells from rodents; primate granule cells commonly have basal dendrites. Seress and Mrzljak5 were the first to show that primate granule cells display basal dendrites in normal brain. Other studies confirmed this observation and showed that many granule cells in monkey have basal dendrites that enter the hilus.6 These basal dendrites have large, complex spines and smaller “stubby” spines. About 10% of granule cells in the monkey dentate gyrus exhibit basal dendrites. Pertinent to this review is the finding that greater numbers of granule cells with hilar basal dendrites are found in the temporal lobes of epileptic humans compared to normal human control tissues.7,8 The remainder of this chapter will focus on the seizure-induced formation of hilar basal dendrites in rodents and the potential significance of hilar basal dendrites in epileptogenesis.
Alterations in the Distribution of GABAA Receptors in Epilepsy
Authors: Houser Carolyn R. , Zhang Nianhui , Peng Zechun 
Published: May 2013

Abstract
Changes in gamma-aminobutyric acid A receptors (GABAAR) in epilepsy are particularly complex and intriguing because of the multiple subunits that can be altered. The numerous GABAAR subunits (α1–6, β1–3, γ1–3, δ, ε, θ, π, and ρ1–3) typically form heteropentameric receptors that are generally composed of two α, two β, and either one γ, δ, or other more minor subunit. The different subunit combinations create a diversity of receptor subtypes that differ in their function, pharmacology, and regional and cellular localization (see refs. 1 and 2 for reviews). Such diversity provides challenges for understanding the functional effects of GABAAR subunit alterations in epilepsy, but it may also offer unique possibilities for treatment of this disorder.
Plasticity of GABAA Receptors Relevant to Neurosteroid Actions
Authors: Mody Istvan 
Published: May 2013

Abstract
It is now widely accepted that phasic (synaptic) and tonic (extrasynaptic) GABAergic influences on neuronal excitability are mediated by different receptors with different pharmacological profiles. This chapter will focus on the plasticity of the neurosteriod-sensitive δ subunit containing gamma-aminobutyric acid A (GABAA) receptors (δ-GABAARs) in animal models of temporal lobe epilepsies (TLE) and its possible consequences for modulating the excitability of the dentate gyrus.
Chloride Homeostasis and GABA Signaling in Temporal Lobe Epilepsy
Authors: Miles Richard , Blaesse Peter , Huberfeld Gilles , Wittner Lucia , Kaila Kai 
Published: May 2013

Abstract
Defects in GABAergic signaling have often been linked to the epilepsies. Suppressing fast inhibition mediated by gamma-aminobutyric acid A (GABAA) receptors initiates interictal-like activities in healthy brain tissue,1,2 and specific subgroups of interneurons seem to be especially sensitive to the neuronal death associated with temporal lobe epileptic syndromes.3–5 However, defects in the neuronal homeostasis of chloride have only recently been linked to epileptiform activities. Intraneuronal levels of chloride control GABAergic signaling postsynaptically.6 So, changes in chloride homeostasis can affect the strength and even the sign of GABAergic signals. We will describe work on tissue from patients with pharmacoresistant epilepsies of the temporal lobe that provided the first insight that chloride homeostasis might be altered in the epilepsies.7,8 We will examine molecules that control chloride homeostasis, evidence that they are modulated by pathological stressors including denervation, anoxia and the sclerotic cell death associated with some focal epilepsies. We ask whether changes in chloride homeostasis contribute to ictal events, arguing that potassium efflux mediated by K-Cl cotransporters may contribute to prolonged ictal excitation. Finally, we examine how differences in chloride regulation may contribute to neonatal epilepsies and ask whether molecules targeting chloride homeostasis might be effective anti-epileptic drugs.
Glia–Neuron Interactions in Ictogenesis and Epileptogenesis
Authors: Vezzani Annamaria , Auvin Stephan , Ravizza Teresa , Aronica Eleonora 
Published: May 2013

Abstract
This chapter reports clinical observations in drug-resistant epilepsies and experimental findings in adult and immature rodent models of seizures and epileptogenesis that causally link brain inflammation to the epileptic process. We discuss the role of specific inflammatory mediators of glia–neuron communication in the etiopathogenesis of seizures.
Glia–Neuron Interactions
Authors: Biagini Giuseppe , Marinelli Carla , Panuccio Gabriella , Puia Giulia , Avoli Massimo 
Published: May 2013

Abstract
Overall, the evidence reviewed in this chapter indicates a complex interaction between glia and neurons in postlesional epilepsies, depicting a scenario similar to that found when analyzing the role of glial cells in the recovery from brain damage. Indeed, astrocytes may exert both pro-epileptogenic and anti-epileptogenic roles through (1) indirect modulation of neuronal function via release of inflammatory cytokines and neurosteroids, or by altering neurotransmitter release, and (2) by directly influencing neuronal activity via release of gliotransmitters.
Genetic Epidemiology and Gene Discovery in Epilepsy
Authors: Ottman Ruth , Risch Neil 
Published: May 2013

Abstract
Over the last two decades, more than 20 genes with a major effect on the risk for human epilepsy have been identified, providing important clues to pathogenic mechanisms and enabling some patients to discover the cause of their disorder.1 However, the genes identified so far affect risk in a very small proportion of patients—primarily those from families consistent with Mendelian modes of inheritance. Most epilepsies occur in the absence of a significant family history, and identifying and characterizing the genetic mechanisms in these complex epilepsies is a major challenge for the next decade.2 Here we discuss the meaning of complex inheritance as it applies to epilepsy, findings from current research, and approaches likely to be advantageous for gene identification in these forms of epilepsy.
Strategies for Studying the Epilepsy Genome
Authors: Ferraro Thomas N. , Dlugos Dennis J. , Hakonarson Hakon , Buono Russell J. 
Published: May 2013

Abstract
Current leading theories on the etiology of the group of diseases called epilepsy implicate both genes and factors in the environment. Genetic research has the potential to identify molecular and cellular mechanisms that can be targeted directly for therapeutic intervention. Although nearly two decades have passed since the discovery of the first epilepsy-causing gene mutation1 and mutations in about a dozen other human genes are now well characterized,2,3 the vast majority of genetic variation that contributes to the development of epilepsy is undiscovered. Thus, there is a critical need to continue to elucidate the epilepsy genome. This chapter will review the comprehensive genome-wide approaches that are being used to achieve this goal.
Sodium Channel Mutations and Epilepsy
Authors: Catterall William A. 
Published: May 2013

Abstract
While many pathophysiological changes contribute to seizure susceptibility, recent work suggests that genetic factors are especially important. Polygenic inheritance patterns have been associated with febrile seizures and idiopathic epilepsy and may be important in determining susceptibility to acquired epilepsy following brain injury. Monogenic inheritance patterns are seen in a number of epilepsies associated with mutations in ligand-gated or voltage-gated ion channels. The genes most frequently associated with epilepsy encode brain sodium channels.
The GABAAγ2(R43Q) Mouse Model of Human Genetic Epilepsy
Authors: Petrou Steven , Reid Christopher A. 
Published: May 2013

Abstract
Epilepsy is a complex disease of neuronal networks; therefore, an understanding of the consequences of genetic dysfunction at clinically relevant temporal and spatial scales requires in vivo models. Although in vitro models have and will continue to shed light on aspects of molecular pathogenesis, gaining knowledge of the effects of mutations on the emergent properties of brain networks is critical if we are to fully understand disease genesis. Genetically modified animal models provide an avenue to investigate disease mechanisms of human mutations at this level of organization. Genetically engineered knockin models, in which the human epilepsy mutation is integrated into the mouse genome and replaces the endogenous allele, are potentially one of the most useful in vivo models for understanding epileptogenesis in genetic epilepsy. These mouse models most closely replicate the human genetic disorder and are becoming the gold standard for investigating the mechanisms underlying specific human epilepsy syndromes.
Gene Interactions and Modifiers in Epilepsy
Authors: Meisler Miriam H. , O'Brien Janelle E. 
Published: May 2013

Abstract
The genetic basis for most cases of human epilepsy remains unknown, in spite of recent successes in identifying the roles of SCN1A and related ion channels. This situation is likely to change dramatically in the near future with the introduction of individual genome sequencing. Using inexpensive, high-throughput next-generation sequencing technology, 〉90% of the 180,000 exons in the human genome can be sequenced from individual samples. The first few exomes published in 2009 and 2010 revealed that every human carries approximately 500 rare amino acid sequence variants not previously described. A spectrum of variation extends from benign variants without functional consequences to mutations causing significant loss of function. By revealing all of their genetic variants, genome sequencing of epilepsy patients will accelerate the discovery of primary disease genes as well as genetic modifiers. The urgent challenge will then be to recognize the subset of amino acid substitutions that change the function of the encoded protein. Functional assays to distinguish between benign and pathogenic variants will be an increasingly important component of epilepsy research in order to interpret the abundant genetic information. Identification of additional epilepsy genes and their genetic modifiers will provide new targets for intervention and should lead to more effective treatments for seizure disorders.
Genes in Infantile Epileptic Encephalopathies
Authors: Depienne Christel , Gourfinkel-An Isabelle , Baulac Stéphanie , LeGuern Eric 
Published: May 2013

Abstract
In this chapter, we will focus on the genes responsible for infantile EEs as the main component of the clinical picture and not on those included in complex phenotypes encountered in metabolic diseases or in contiguity syndromes due to large chromosomal abnormalities. Indeed, the association of EE with a dysmorphy or extraneurological symptoms should lead to specific metabolic or cytogenetic investigations. In the first part of this chapter, we will review the genes involved in early infantile epileptic encephalopathies (EIEEs). Although the mutations in these genes are rare, their screening has to be integrated into a rational diagnostic strategy. It is particularly important to rule out genetic etiologies since there is a risk of the disease recurring in the family. In this review, we will focus on DS as an example of a genetically determined infantile EE to emphasize the difficulties and pitfalls that might be encountered in such diseases.
Developing Models of Aristaless-Related Homeobox Mutations
Authors: Marsh Eric D. , Golden Jeffrey A. 
Published: May 2013

Abstract
Mutations in the Aristaless-related homeobox gene (ARX) have been causally linked to a variety of neurological conditions, particularly infantile spasms syndrome. ARX is a developmentally regulated homeobox transcription factor with expression both in the ganglionic eminence and in the cortical ventricular zone early in development.1 Postnatally, the expression pattern is restricted to GABAergic (gamma-aminobutyric acid) neurons in the cortex and basal ganglia. During development, ARX functions primarily as a transcriptional repressor2: modulating migration and fate specification of interneurons and controlling ventricular zone proliferation. How loss of function of ARX leads to an epilepsy phenotype is poorly understood. Three genetically modified mice lines have been generated3–5 to address this issue. These models each develop epilepsy, and all have changes in interneuron subtype patterns strongly implicating alterations of interneuron development as a cause of epilepsy. Analysis of these models will both further the molecular understanding of the function of ARX and allow dissection of the pathophysiological properties of the ARX-related epilepsies. This chapter will review the current knowledge of the function of Arx, the Arx mouse models, and discuss how these models can lead to a better understanding of the role of interneuron loss in the development of epilepsy during early childhood.