Showing papers in "Advances in Neurology in 1999"

Neuronal networks in the genetically epilepsy-prone rat.

Abstract: It is now possible to develop a dynamic neuronal network model for generalized convulsive seizures because of in vivo data recently obtained in a naturally occurring epilepsy model--the genetically epilepsy-prone rats (GEPR-9s). GEPR-9s exhibit audiogenic seizures (AGS) that consist of a sequence of discrete behavioral phases (i.e., wild running, clonus-tonus, and post-ictal depression). The neuronal firing changes in most nuclei implicated in the network during each phase of AGS in behaving GEPR-9s have been examined. The inferior colliculus is critical in AGS initiation, because extensive firing increases in inferior colliculus are observed preceding seizure initiation. The deep layers of superior colliculus (DLSC) are crucial to wild running, based on the emergence of tonic firing of DLSC neurons just preceding this phase. The pontine reticular nucleus (PRF) and periaqueductal gray (PAG) are critical to the clonic-tonic phase, because tonic firing patterns appear in these neurons just prior to this phase. During post-ictal depression all areas except the PRF are quiescent. These temporal relationships suggest that each nucleus plays a specific hierarchic role in each discrete convulsive behavior. Generalized tonic-clonic seizure behavior observed in human epilepsy, in GEPR-9s, and in other seizure models is likely to involve similar neuronal network components. The neurotransmitter mechanisms subserving the abnormal neuronal responses in the GEPR-9 neuronal network involve an increased availability of glutamate and a decrease in the effectiveness of gamma-aminobutyric acid (GABA) in many brain regions. Focal modification of the effects of GABA, glutamate, norepinephrine, or serotonin also modulates the nuclei of the network differentially. Together, these data reveal the anatomic, neurotransmitter, and neurophysiologic mechanisms of the neuronal network hierarchy in GEPR-9s, which is currently the most completely developed of any generalized convulsive model. Differential effects of anticonvulsants on the AGS phases and concomitant differential modifications of neuronal firing are observed on neurons in these network nuclei. With nearly complete identification of the network nuclei, the differential effects of these anticonvulsant drugs on different aspects of neuronal firing in different brain sites indicate that this experimental approach can likely identify the most sensitive therapeutic target for these agents. This concept is potentially vital to developing the most selective treatment of different convulsive behaviors occurring in human epilepsy. The neuronal network for AGS does not require brain structures rostral to the midbrain for seizure expression. However, the forebrain is recruited into an expanded seizure network through AGS repetition ("kindling"), resulting in prolonged AGS, post-tonic clonus, and epileptiform electrographic cortical abnormalities. AGS kindling produces network expansion into medial geniculate body (MGB) and amygdala and involves neuronal firing increases in MGB.

Molecular properties of brain sodium channels: an important target for anticonvulsant drugs.

Abstract: The voltage-gated sodium channels that are responsible for action potential generation in central neurons are important targets for the actions of antiepileptic drugs. These channels consist of a complex of three glycoprotein subunits: a pore-forming alpha subunit of 260 kd associated noncovalently with a beta 1 subunit of 36 kd and disulfide-linked to a beta 2 subunit of 33 kd. The alpha subunit forms a functional voltage-gated sodium channel by itself, whereas the beta 1 and beta 2 subunits modulate channel gating. The beta 1 and beta 2 subunits also have immunoglobulin-like folds in their extracellular domains that are predicted to interact with extracellular proteins. The alpha subunit is comprised of four homologous domains containing six transmembrane alpha helices (S1 through S6) and additional membrane-associated segments (SS1/SS2). The S4 segments in each domain function as voltage sensors for voltage-dependent activation of the sodium channel. The S5 and S6 segments in each domain and the short SS1/SS2 segments between them form the pore of the channel. The intracellular loop between domains III and IV forms the inactivation gate, which folds into the pore and occludes it within 1 msec of channel opening. The activity of brain sodium channels in modulated by protein phosphorylation G proteins. Activation of muscarinic acetylcholine receptors in hippocampal neurons slows the inactivation of sodium channels and reduces peak sodium currents through activation of protein kinase C (PKC) phosphorylation of sites in the inactivation gate and the intracellular loop between domains I and II of the alpha subunit. Other neurotransmitters that activate the PKC pathway are likely to have similar effects. Activation of D1-like dopamine receptors in hippocampal neurons reduces peak sodium currents through activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase phosphorylation of sites in the intracellular loop between domains I and II. Modulation by PKC and cAMP-dependent protein kinase is convergent--phosphorylation of the inactivation gate by PKC is required before phosphorylation of sites in the intracellular loop between domains I and II can reduce peak sodium currents. Brain sodium channels are also modulated by G proteins. Activation of endogenous G protein-coupled receptors causes negative shifts in the voltage dependence of sodium channel activation and inactivation. Overexpression of G protein beta gamma subunits induces persistent sodium currents. Regulation of sodium channel function by these multiple pathways can produce a flexible tuning of electrical excitability of central neurons in response to neurotransmitters, hormones, and second messengers. The antiepileptic drugs phenytoin, carbamazepine, and lamotrigine inhibit brain sodium channels substantially at clinically relevant concentrations. Their inhibition of sodium channels is increased by depolarization because they bind preferentially to the inactivated state of the channels. This effect increases the inhibition of sodium channels in depolarized tissue at the center of an epileptic focus. Local anesthetics also inhibit sodium channels by preferential binding to the inactivated state. Site-directed mutagenesis experiments show that antiepileptic drugs and local anesthetics bind to a common receptor site in the pore of the channel that is formed in part by three critical amino acid residues in transmembrane segment S6 in domain IV. Mutations in these amino acid residues prevents preferential binding to the inactivated state and thereby greatly reduces the affinity for inhibition of sodium channels by these drugs. Knowledge of the structure-function relationships for drug binding at this receptor site may open the way to development of novel classes of antiepileptic drugs.

GABA is the principal fast-acting excitatory transmitter in the neonatal brain.

Abstract: gamma-aminobutyric acid (GABA) is the principal neurotransmitter of inhibition in the adult mammalian brain. However, at early stages of development, including the embryonic period and first week of postnatal life, GABA plays the role of main neurotransmitter of excitation. The paradoxical excitatory effect of GABA is caused by an inverted chloride gradient and, therefore, a depolarizing direction of GABA type A (GABAA) receptor mediated responses. In addition, another type of GABAergic inhibition mediated by postsynaptic GABA type B (GABAB) receptors is not functional at early stage of life. In the neonatal rat hippocampus, GABA, acting via GABAA receptors, activates voltage-gated sodium and calcium channels and potentiates the activity of N-methyl-D-aspartate (NMDA) receptors by reducing their voltage-dependent Mg2+ block. The temporal window when GABA exerts excitatory actions coincides with a particular pattern of activity of hippocampal neuronal network that is characterized by periodical giant depolarizing potentials (GDPs) reminiscent of interictal-like epileptiform discharges. Recent studies have shown that GDPs result from the synchronous discharge of GABAergic interneurons and principal glutamatergic pyramidal cells, and they are mediated by the synergistic excitatory actions of GABAA and glutamate receptors. GDPs provide synchronous intracellular Ca2+ oscillations and may, therefore, be implicated in hebbian modulation of developing synapses and activity-dependent formation of the hippocampal network.

Epidemiology of Parkinson's disease.

Abstract: Publisher Summary This chapter discusses the epidemiology of Parkinson's disease (PD). Classically, PD refers to progressive parkinsonism caused by loss of pigmented aminergic brainstem neurons without an identifiable cause, while parkinsonism refers simply to the syndrome of bradykinesia, resting tremor, rigidity and postural reflex impairment. Over nearly two centuries, Parkinson's clinical description has provided the framework for clinical investigations, including epidemiologic ones. Descriptions of PD were limited to selected clinical settings until the middle of the 20th century. Since then, epidemiologic approaches have been used not only to investigate the population distribution of PD, but also as a way to glean clues as to the cause of this “idiopathic” disorder. Because PD is relatively infrequent, a large base population must be surveyed to identify sufficient numbers of cases for a study. In some instances, PD cases can be identified through health service rosters within defined geographic areas or in enumerated populations. In others, cases of PD are sought independently of the health care system, such as through door-to-door surveys. While the latter approach is theoretically least likely to exclude cases, the time and cost involved are also greatest using this approach.

The role of neural activity in synaptic development and its implications for adult brain function

Abstract: In much of the developing nervous system, electrical activity guides the formation of neural connections, with lasting effects on adult brain function. Epilepsy, a defect in neuronal excitability, might result from abnormal patterns of activity in the young brain. Many connections are organized by selective stabilization of synapses when they are activated simultaneously on the same postsynaptic cell during a sensitive period in early life. This process often involves calcium entry through the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. The magnitude of the current passed by this receptor depends on its subunit composition, which varies with age and brain region. Although receptor configurations that admit large calcium currents are permissive of synaptic plasticity, they also increase neural vulnerability to excitotoxic cell death. In most regions of developing brain, activity that can drive NMDA receptors initially is low and increases with maturation. Thus, the replacement of NMDA receptors that flux large calcium currents during early periods of synaptic organization with NMDA receptor subtypes that flux less calcium as synapses become more active, more effective, and less plastic allows maturing neurons to maintain optimal levels of intracellular calcium in the face of drastic developmental changes in their inputs. We have proposed that this transition in NMDA receptors from high to low calcium permeabilities is itself activity dependent. This idea is supported by data showing that many synaptic proteins, including receptor subunits, can be regulated by activity. Cultured cerebellar granule neurons require NMDA receptor stimulation for survival and differentiation, which may replicate the activation provided by the arrival of mossy fiber innervation in vivo. In these cultures, chronic depolarization and glutamate or NMDA treatment induces more mature NMDA receptor subunit expression patterns and function and also increases the expression of several gamma-aminobutyric acid type A (GABAA) receptor subunits, changing that receptor's function. In addition, evidence from in vivo studies indicates that synaptic maturation itself may depend on NMDA receptor activity. During the formation of topographic connections between the retina and superior colliculus (SC) of young rats, chronic local application of the competitive NMDA receptor antagonist +2-amino-5-phosphonovalerate (D-APV) blocks the normal developmental up-regulation of NMDA receptor subunit 1 (NR1) mRNA and nitric oxide synthase activity, as well as maturation of calcium and calmodulin-dependent kinase distribution, activity, and substrate phosphorylation. Together, these recent molecular findings suggest that chronic seizure disorders could result from any of a variety of early developmental events. Any disturbance that locally perturbs regulation of NMDA receptors or the temporal correlations in synaptic activity that drive these receptors has the potential to alter the normal development of local circuitry and the critical balance of inhibition and excitation required to contain seizure activity.

AMPA receptors in epilepsy and as targets for antiepileptic drugs

Abstract: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are key mediators of seizure spread in the nervous system and represent promising targets for antiepileptic drugs. There is emerging evidence that AMPA receptors may play a role in epileptogenesis and in seizure-induced brain damage. This evidence suggests that AMPA receptor antagonists could have broad utility in epilepsy therapy. Regional, developmental, and disease-associated variations in AMPA receptors produced by differential expression of AMPA receptor subunits and variations in posttranscriptional processing, including alternative splicing and pre-mRNA editing, provide a diversity of functionally distinct AMPA receptor isoforms that allow opportunities for selective drug targeting. Four types of AMPA receptor antagonist are discussed in this chapter: (a) competitive AMPA recognition site antagonists, including those of the quinoxalinedione and newer nonquinoxalinedione classes, (b) 2,3-benzodiazepine noncompetitive (allosteric) antagonists, (c) desensitization enhancing antagonists, exemplified by SCN-, and (d) antagonists of Ca(2+)-permeable AMPA receptors, including polyamine amide arthropod toxins and their synthetic analogues. Competitive and noncompetitive AMPA receptor antagonists are broad-spectrum anticonvulsants in animal seizure models. Their effectiveness and safety for humans remain to be determined. There is evidence that these antagonists can potentiate the antiseizure activity of N-methyl-D-aspartate (NMDA) receptor antagonists and conventional antiepileptic drugs. This evidence suggests that the preferred use of AMPA receptor antagonists may be in combination therapies. Agents that enhance desensitization may have advantages in comparison with other AMPA receptor antagonists to the extent that they preferentially block high-frequency synaptic signaling and avoid depressing AMPA receptors on interneurons, which would lead to disinhibition and enhanced excitability. Evidence has accumulated that Ca(2+)-permeable AMPA receptors (those lacking the edited GluR2 subunit) may play a role in epileptogenesis and the brain damage occurring with prolonged seizures. Because Ca(2+)-permeable AMPA receptors are predominately expressed in gamma-aminobutyric acid (GABA)ergic interneurons, it is hypothesized that some forms of epilepsy might be caused by reduced GABA inhibition resulting from Ca(2+)-permeable AMPA receptor-mediated excitotoxic death of interneurons. It is further proposed that drugs that selectively target Ca(2+)-permeable AMPA receptors might have antiepileptogenic and neuroprotective properties. Certain polyamine toxins and their analogues are channel-blocking AMPA receptor antagonists that selectively inhibit Ca(2+)-permeable AMPA receptors. These substances might give clues to the development of such antagonists.

Neuronal circuitry of thalamocortical epilepsy and mechanisms of antiabsence drug action.

Abstract: Powerful mechanisms exist within the thalamus that lead to the promotion of synchronous and phasic 3 Hz neuronal activity. These mechanisms include robust burst-firing capability of thalamic neurons, recurrent excitatory and inhibitory synaptic connectivity, and long-lasting and powerful inhibitory synaptic responses arising from activity in thalamic reticular neurons and mediated by gamma-aminobutyric acid (GABA) receptors. The 3 Hz thalamic synchronization appears to arise from a perturbation of a physiologic, higher frequency spindle oscillation. Two currently available antiabsence medications interact with this circuitry with the net result of decreased synchronization, largely through reduction in inhibitory output from the thalamic reticular nucleus. Ethosuximide blocks T-type calcium channels and thus reduces the ability of thalamic neurons to fire bursts of spikes, thereby reducing inhibitory (and excitatory) output within the circuit. By contrast, clonazepam enhances recurrent inhibitory strength within the reticular nucleus. This results in a decreased ability of neighboring inhibitory neurons to fire synchronously and produce the powerful inhibitory synaptic responses that are required for network synchronization.

Traditional and complementary therapies in Parkinson's disease.

Abstract: Parkinson's disease has existed in different parts of the world since ancient times. The first clear description is found in the ancient Indian medical system of Ayurveda under the name Kampavata. Traditional therapies in the form of herbal preparations containing anticholinergics, levodopa, and monoamine oxidase inhibitors were used in the treatment of PD in India, China, and the Amazon basin. Scientific reevaluation of these therapies may be valuable, as shown in the case of Mucuna pruriens and Banisteria caapi. Complementary therapies such as massage therapy, biofeedback, and acupuncture may have beneficial effects for patients and deserve further study.

Role of metabotropic glutamate receptors in epilepsy.

Abstract: Considerable information is available regarding the role of ionotropic glutamate receptors in the generation of interictal spikes. Progress in the study of metabotropic glutamate receptors (mGluRs) makes clear that activation of these receptors can contribute greatly to seizure discharges and epileptogenesis. The effects of activation of the different mGluR subgroups on neuronal hypersynchrony and the initiation and propagation of seizure discharges in hippocampal slices are discussed herein. To help one understand the mechanisms that underlie these effects, information regarding the action of mGluRs on cellular and synaptic properties is summarized. The data bring to the forefront the critical role of mGluRs in epilepsy and emphasize the anticonvulsant effects of group II and III mGluR activation as opposed to the convulsant action of group 1, which elicits seizure discharges and epileptogenesis in experimental models.

Age-dependent vulnerability to seizures.

Abstract: Seizure disorders frequently occur early in life Seizures are classified as reactive, symptomatic, or idiopathic depending on whether their cause can be identified Reactive seizures are the result of acute environmental perturbations Early in life, many stressors can produce seizures and the ultimate outcome may depend on the particular precipitating factor and its intensity Febrile convulsions are the most common reactive seizures, although they must be differentiated from symptomatic seizures precipitated by fever Symptomatic seizures are often associated with varying degrees of central nervous system (CNS) insults, including congenital malformations and metabolic storage diseases of the gray matter These seizures may have age-specific characteristics and may at times be difficult to treat with conventional antiepileptic treatments To develop a better understanding of the pathophysiology of seizures early in life, we have extensively used animal models of epilepsy In this chapter, we report our findings with a rat model of developmental cortical dysplasias produced by intrauterine injections of methylazoxymethanol acetate These rats are more susceptible to kainic acid, flurothyl, and hyperthermic seizures than normal rats Rats with severe cortical dysplasia are most susceptible to seizures We have also studied the mechanisms involved in the control of seizures during development because status epilepticus is more prevalent in infants than in adults Our data suggest that the substantia nigra may play a crucial role in status epilepticus as a function of age In the adult substantia nigra two regions mediate opposing effects on seizures following infusions of gamma-aminobutyric acid type A (GABAA) agents One region is located in the anterior substantia nigra, and muscimol infusions in this region mediate anticonvulsant effects The second region is in the posterior substantia nigra, and here muscimol infusions produce proconvulsant effects In situ hybridization data demonstrate that, at the cellular level, neurons in the two substantia nigra regions differ in the amount of hybridization grains for GABAA receptor alpha 1 and gamma 2L subunit mRNAs In developing male rats, only the "proconvulsant" region is present up to the age of 21 days The transition from the immature to mature substantia nigra mediated seizure control occurs between age 25 and 30 days The identification of age-dependent functional networks involved in the containment of seizures may lead to possible new pharmacologic strategies to control seizures, thus aiding the development of age-appropriate treatments of seizure disorders

Synaptic plasticity in kindling.

Abstract: Kindling is an experimental model of epilepsy resulting from progressive activity-dependent changes in neuronal structure and function. During kindling, pathologic changes occur at various levels of organization of the nervous system, ranging from altered gene-expression in individual neurons to the loss of specific neuronal populations and the rearrangement of synaptic connections. This chapter summarizes recent findings about the long-lasting (plastic) nature of the alterations at the level of single neurons with emphasis on the role of altered excitatory and inhibitory amino acid receptors. The modified synaptic ligand-gated ion channels (i.e., "epileptic receptors") may ultimately be responsible for the kindling epileptogenesis.

Developmental neuroplasticity : Roles in early life seizures and chronic epilepsy

Abstract: Both clinical and experimental studies suggest that the immature nervous system is unusually susceptible to seizures during critical periods in postnatal life. A late onset of gamma-aminobutyric acid (GABA)-mediated synaptic inhibition could conceivably play a contributing role in this phenomenon. Numerous studies have shown that neural systems that use GABA in the neonatal brain are different than those of adulthood. GABA is an excitatory neurotransmitter that likely plays a neurotrophic role in neuronal differentiation. Other reports suggest that unique, possibly transient, GABAergic interneuron populations exist in the embryonic and neonatal nervous system. At these early times in development, the immature nervous system is remarkably resistant to seizure generation. However, as the hippocampus and neocortex enter the critical period of enhanced seizure susceptibility, inhibitory GABA systems mature rapidly. At this time, blockade of GABA type A (GABAA) receptors produce unusually severe seizure discharges. In hippocampus, concurrent exuberant outgrowth of recurrent excitatory axon collaterals and synapses appear to play a role in the generation of these seizures. As the hippocampus matures, these axons are morphologically remodeled and nearly 50% of branches within arbors are pruned. This pruning of axon branches corresponds in time with the decrease in seizure susceptibility that characterizes adulthood. Developmental remodeling of neuronal connectivity is a common feature of most areas of the central nervous system. Results from an audiogenic seizure model of early onset epilepsy suggest that prevention of axon arbor remodeling by transient sensory deprivation can lead to a permanent overinnervation of target nuclei and chronic seizure susceptibility. Early life seizures may have a similar effect. Recent results in one model have shown that repeated seizures induced by intrahippocampal injections of tetanus toxin during a critical period results in a chronic epilepsy. Future studies should attempt to determine if the synchronized discharging of early-life seizures prevents the remodeling of neuronal connectivity that normally takes place during postnatal development and results in an overinnervated and chronically hyperexcitable hippocampus.

Single-gene models of epilepsy.

Abstract: Single-gene models of epilepsy present valuable opportunities to isolate and experimentally reproduce gene mutations for human seizure disorders, to test molecular mechanisms of epileptogenesis, and to explore strategies to correct early hyperexcitability defects in the developing brain. Although not all inherited epilepsies are monogenic, analysis of epileptic phenotypes in spontaneous and transgenic mouse mutants is beginning to define the kinds of molecular defects favoring inherited aberrant synchronization in central neurons. The range of genes identified shows that rather than arising from a few superfamilies that regulate membrane excitability, the gene products are drawn from many categories involved in widely diverse functions of the cell. Although some primary defects directly alter membrane electrogenesis and neurotransmitter signaling at synapses, others are too far removed from these processes to allow one to visualize the steps by which they promote epileptogenesis. There is now clear evidence that several and probably most epilepsy genes entrain specific patterns of secondary cellular plasticity during brain development. It can be predicted that these downstream rearrangements may partially account for the delayed temporal onset and other progressive features of epilepsy syndromes. Experimental alterations that target the mutant gene product and patterns of secondary network plasticity provide a basis for future strategies to reverse the epileptogenic process.

The molecular genetic bases of the progressive myoclonus epilepsies.

Abstract: Among the epilepsies, the progressive myoclonus epilepsies (PMEs) form a heterogeneous group of rare diseases characterized by myoclonus, epilepsy, and progressive neurologic deterioration, particularly dementia and ataxia. The success of the Human Genome Project and the fact that most PMEs are inherited through a mendelian or mitochondrial mode have resulted in important advances in the definition of the molecular basis of PME. The gene defects for the most common forms of PME (Unverricht-Lundborg disease, the neuronal ceroid lipofuscinoses, Lafora disease, type I sialidosis, and myoclonus epilepsy with ragged-red fibers) have been either identified or mapped to specific chromosome sites. Unverricht-Lundborg disease has been shown to be caused by mutations in the gene that codes for cystatin B, an inhibitor of cysteine protease. The most common mutation in Unverricht-Lundborg disease is an expansion of a dodecamer repeat located in a noncoding region upstream of the transcription start site of the cystatin B gene, making it the first human disease associated with instability of a dodecamer repeat. Juvenile neuronal ceroid lipofuscinosis is caused by mutations in the CLN3 gene, a gene of unknown function that encodes a 438-amino-acid protein of possible mitochondrial location. Other forms of neuronal ceroid lipofuscinosis that occur as PME and Lafora disease have been mapped by means of linkage analysis, but the corresponding gene defects remain unknown. Sialidosis has been shown to be caused by mutations in the sialidase gene, and myoclonus epilepsy with ragged-red fibers is well known to be caused by mutations in the mitochondrial gene that codes for tRNA(Lys). How the different PME gene defects described produce the various PME phenotypes, including epileptic seizures, remains unknown. The development of animal models that bear these mutations is needed to increase our knowledge of the basic mechanisms involved in the PMEs. This knowledge should lead to the development of new and effective forms of therapy, which are especially lacking for the PMEs.

Mapping and positional cloning of common idiopathic generalized epilepsies: juvenile myoclonus epilepsy and childhood absence epilepsy.

Abstract: Among the 40 to 100 million persons with epilepsy worldwide and the 2 to 2.5 million persons with epilepsies in the United States, approximately 50% have generalized epilepsies. Among all epilepsies, the most common are juvenile myoclonus epilepsy (JME) with 10% to 30% of cases, childhood absence epilepsy (CAE) with 5% to 15% of cases, and pure grand mal on awakening with 22% to 37% of cases. In the last decade, six different chromosomal loci for common generalized epilepsies have been identified. These include two separate loci for JME in chromosomes 6p and 15q. The epilepsy locus in chromosome 6p expresses the phenotypes of classic JME, pure grand mal on awakening, and possibly JME mixed with absences. Two separate loci also are present for pyknoleptic CAE, namely, CAE that evolves to JME in chromosome 1p and CAE with grand mal in chromosome 8q24. Pandolfo et al. from the Italian League Against Epilepsy have reported two other putative susceptibility loci for idiopathic generalized epilepsies, namely, grand mal and generalized spike waves 35l in chromosome 3p and generalized epilepsies with febrile convulsions, grand mal, JME, absences, and electroencephalographic spike waves in 8q24. This chapter reports on the debate concerning whether there may be two separate epilepsy loci in chromosome 6p, one in the HLA region and one below HLA. The chapter then discusses the progress made in our laboratories as a result of the Genetic Epilepsy Studies (GENES) International Consortium. We discuss (a) the 2 to 6 cM critical region for classic JME located some 20 cM below HLA in chromosome 6p, (b) the 7-cM area for pyknoleptic CAE that evolves to JME in chromosome 1p, and (c) the 3.2 cM area for pyknoleptic CAE with grand mal and irregular 3 to 4 Hz spike waves in chromosome 8q24. We discusses efforts underway to refine the genetic map of JME in chromosome 6p11 and the advances in physical mapping and positioning of candidate genes, such as the gamma-aminobutyric acid receptor gene, the potassium channel gene of the long-QT family (KvLQT), named KCNQ3, and the human homologue of the mouse jerky gene for CAE in chromosome 8q24 and JME in chromosome 6p11.

Basic mechanisms of status epilepticus.

Abstract: This chapter reviews two main aspects of the basic mechanisms of status epilepticus--acute factors, which are important in inducing status epilepticus in an in vitro brain slice model of status epilepticus, and the acute and chronic epileptogenic consequences of status epilepticus. Status epilepticus is difficult to produce in vitro in normal extracellular medium. This suggests that seizure-terminating mechanisms are normally quite robust. To produce long- duration, self-sustained epileptic discharges in vitro, we have found it necessary to include reciprocally connected entorhinal cortex with our hippocampal slices. Doing so closes the normal excitatory limbic loop in the brain. We found incorporation of the full loop in our brain-slice preparations necessary to bring about epileptic discharges of long duration that fit the definition of status epilepticus. Reentrant activation from distant sites may be necessary for maintenance of status epilepticus-like activity of long duration. Similar requirements may exist for generalized tonic-clonic status epilepticus discharges, but as yet no data support or refute this hypothesis. There are both acute and chronic consequences of an episode of status epilepticus. Acute consequences are alterations in membrane potential and membrane properties of hippocampal pyramidal cells accompanied by alterations in neurotransmitter-activated conductances and receptor expression. Some of these acute alterations in receptor and transmembrane iongradient associated with status epilepticus may be critically involved in the development of drug resistance during the late stages of status epilepticus. Long-term consequences of status epilepticus in the limbic system include alterations in patterns of expression of neurotransmitter receptors and in the function of excitatory and inhibitory synapses, cell loss, and circuit rearrangements within the limbic system. An episode of status epilepticus that involves the limbic system clearly elicits brain damage, at least among adult animals. This brain damage can contribute to the development of epilepsy, or a condition of recurrent, spontaneous seizures. Conversely, development of an epileptic condition enhances the susceptibility of the limbic system to trigger status epilepticus discharges.