Animal Models of Limbic Epilepsies: What Can They Tell Us?

In this review, we have provided an overview of the implementation and characteristics of some of the most prevalent models of temporal lobe epilepsy in use in laboratories around the world today. These include spontaneously seizing models with status epilepticus as the initial precipitating injury (including the kainate, pilocarpine, and electrical stimulation models), kindling, and models of drug refractoriness. These models share various features with one another, and also differ in many aspects, providing a broader representation of the full spectrum of clinical limbic epilepsies. We have also provided a brief introduction into how animal models of temporal lobe epilepsy facilitate use of modern state-of-the-art techniques in neurobiology to address critical questions in the pathogenesis of epilepsy.

[1]  J. Wada,et al.  Spontaneous recurrent seizure state induced by daily electric amygdaloid stimulation in Senegalese baboons (Papio papio) , 1976, Neurology.

[2]  M. Barton,et al.  Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy , 2001, Epilepsy Research.

[3]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. 3. Mechanisms. , 1972, Electroencephalography and clinical neurophysiology.

[4]  Karen L. Smith,et al.  Novel Hippocampal Interneuronal Subtypes Identified Using Transgenic Mice That Express Green Fluorescent Protein in GABAergic Interneurons , 2000, The Journal of Neuroscience.

[5]  Wolfgang Löscher,et al.  Animal models of intractable epilepsy , 1997, Progress in Neurobiology.

[6]  W. Löscher,et al.  Is amygdala kindling in rats a model for drug-resistant partial epilepsy? , 1986, Experimental Neurology.

[7]  J. Wada,et al.  Secondarily generalized convulsive seizures induced by daily amygdaloid stimulation in rhesus monkeys , 1978, Neurology.

[8]  G. Holmes,et al.  Transfer following rapid kindling in the prepubescent rat , 1989, Epilepsy Research.

[9]  A. Draguhn,et al.  Strategies for the Development of Drugs for Pharmacoresistant Epilepsies , 1994, Epilepsia.

[10]  P. Mangan,et al.  The Midline Thalamus: Alterations and a Potential Role in Limbic Epilepsy , 2001, Epilepsia.

[11]  Burnham Wm Primary and "transfer" seizure development in the kindled rat. , 1975 .

[12]  L. Tsai,et al.  Abnormal Morphological and Functional Organization of the Hippocampus in a p35 Mutant Model of Cortical Dysplasia Associated with Spontaneous Seizures , 2001, The Journal of Neuroscience.

[13]  K. Holloway,et al.  Human Neuronal γ-Aminobutyric AcidA Receptors: Coordinated Subunit mRNA Expression and Functional Correlates in Individual Dentate Granule Cells , 1999, The Journal of Neuroscience.

[14]  M. Vreugdenhil,et al.  Modulation of Sodium Currents in Rat CA1 Neurons by Carbamazepine and Valproate After Kindling Epileptogenesis , 1999, Epilepsia.

[15]  D. Mcintyre,et al.  Kindling and the mirror focus. , 2001, International review of neurobiology.

[16]  W. Löscher Current status and future directions in the pharmacotherapy of epilepsy. , 2002, Trends in pharmacological sciences.

[17]  T. Babb,et al.  Synaptic reorganization by mossy fibers in human epileptic fascia dentata , 1991, Neuroscience.

[18]  R. S. Sloviter,et al.  Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. , 1987, Science.

[19]  D. Mcintyre,et al.  Kindling in the perirhinal cortex , 1993, Brain Research.

[20]  L. Covolan,et al.  Cell damage and neurogenesis in the dentate granule cell layer of adult rats after pilocarpine- or kainate-induced status epilepticus. , 2000, Hippocampus.

[21]  Y. Ben-Ari,et al.  Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy , 1985, Neuroscience.

[22]  W. Löscher,et al.  Characterization of Phenytoin‐Resistant Kindled Rats, a New Model of Drug‐Resistant Partial Epilepsy: Comparison of Inbred Strains , 1998, Epilepsia.

[23]  D. Mcintyre,et al.  FAST and SLOW amygdala kindling rat strains: comparison of amygdala, hippocampal, piriform and perirhinal cortex kindling , 1999, Epilepsy Research.

[24]  G. V. Goddard,et al.  A permanent change in brain function resulting from daily electrical stimulation. , 1969, Experimental neurology.

[25]  W. Löscher,et al.  Effects of the Novel Antiepileptic Drug Levetiracetam on Spontaneous Recurrent Seizures in the Rat Pilocarpine Model of Temporal Lobe Epilepsy , 2002, Epilepsia.

[26]  D. Coulter Mossy Fiber Zinc and Temporal Lobe Epilepsy: Pathological Association with Altered “Epileptic”γ‐Aminobutyric Acid A Receptors in Dentate Granule Cells , 2000, Epilepsia.

[27]  D. Geschwind,et al.  Dentate Granule Cell Neurogenesis Is Increased by Seizures and Contributes to Aberrant Network Reorganization in the Adult Rat Hippocampus , 1997, The Journal of Neuroscience.

[28]  A. Schinkel,et al.  P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. , 1996, The Journal of clinical investigation.

[29]  Z. Bortolotto,et al.  Seizures produced by pilocarpine in mice: A behavioral, electroencephalographic and morphological analysis , 1984, Brain Research.

[30]  D. Mcintyre,et al.  Cortical spreading depression reversibly disrupts convulsive motor seizure expression in amygdala-kindled rats , 1999, Neuroscience.

[31]  T. Babb,et al.  Circuit Mechanisms of Seizures in the Pilocarpine Model of Chronic Epilepsy: Cell Loss and Mossy Fiber Sprouting , 1993, Epilepsia.

[32]  N. Barbaro,et al.  MDR1 Gene Expression in Brain of Patients with Medically Intractable Epilepsy , 1995, Epilepsia.

[33]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. II. Motor seizure. , 1972, Electroencephalography and clinical neurophysiology.

[34]  M. Okazaki,et al.  Hippocampal mossy fiber sprouting and synapse formation after status epilepticus in rats: Visualization after retrograde transport of biocytin , 1995, The Journal of comparative neurology.

[35]  H. Beck,et al.  Effect of phenytoin on sodium and calcium currents in hippocampal CA1 neurons of phenytoin-resistant kindled rats , 2002, Neuropharmacology.

[36]  R. Racine,et al.  Kindling mechanisms: Current progress on an experimental epilepsy model , 1986, Progress in Neurobiology.

[37]  G. Regesta,et al.  Clinical aspects and biological bases of drug-resistant epilepsies , 1999, Epilepsy Research.

[38]  W Wisden,et al.  The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[39]  M. E. Corcoran,et al.  Role of the Forebrain Commissures in Amygdaloid Kindling in Rats , 1978, Epilepsia.

[40]  I. Módy,et al.  Lasting potentiation of inhibition is associated with an increased number of gamma-aminobutyric acid type A receptors activated during miniature inhibitory postsynaptic currents. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. Coulter,et al.  Differential epilepsy-associated alterations in postsynaptic GABA(A) receptor function in dentate granule and CA1 neurons. , 1997, Journal of neurophysiology.

[42]  D. Lowenstein,et al.  Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[43]  D. Coulter,et al.  Selective changes in single cell GABAA receptor subunit expression and function in temporal lobe epilepsy , 1998, Nature Medicine.

[44]  G. Cascino,et al.  Mossy fiber synaptic reorganization in the epileptic human temporal lobe , 1989, Annals of neurology.

[45]  F. Morrell Experimental focal epilepsy in animals. , 1959, Archives of neurology.

[46]  L. Goodman,et al.  Comparative assay of an antiepileptic drugs by psychomotor seizure test and minimal electroshock threshold test. , 1953, The Journal of pharmacology and experimental therapeutics.

[47]  A. Phillips,et al.  Spontaneous seizures generated in rats by kindling: A preliminary report , 1975 .

[48]  M. Fromm,et al.  P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. , 2000, International journal of clinical pharmacology and therapeutics.

[49]  J. Noebels,et al.  Targeting Epilepsy Genes , 1996, Neuron.

[50]  J. Burchfiel,et al.  Facilitation and antagonism of kindled seizure development in the limbic system of the rat. , 1981, Electroencephalography and clinical neurophysiology.

[51]  CR Houser,et al.  Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[52]  D. Mcintyre,et al.  Differential Expression of α1, α2, α3, and α5 GABAA Receptor Subunits in Seizure-Prone and Seizure-Resistant Rat Models of Temporal Lobe Epilepsy , 1999, The Journal of Neuroscience.

[53]  C. Wahlestedt,et al.  Antisense oligonucleotide strategies in neuropharmacology. , 1994, Trends in pharmacological sciences.

[54]  Z. Bortolotto,et al.  Review: Cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: A novel experimental model of intractable epilepsy , 1989, Synapse.

[55]  D. Coulter,et al.  Epilepsy-associated plasticity in gamma-aminobutyric acid receptor expression, function, and inhibitory synaptic properties. , 2001, International review of neurobiology.

[56]  J. Pinel,et al.  Experimental epileptogenesis: Kindling-induced epilepsy in rats , 1978, Experimental Neurology.

[57]  W. Löscher,et al.  THE ROLE OF THE PIRIFORM CORTEX IN KINDLING , 1996, Progress in Neurobiology.

[58]  M. During,et al.  Viral-based gene transfer to the mammalian CNS for functional genomic studies , 2001, Trends in Neurosciences.

[59]  B. Hermann,et al.  Behavioral Problems and Social Competence in Children with Epilepsy , 1981, Epilepsia.

[60]  S. Moshé The effects of age on the kindling phenomenon. , 1981, Developmental psychobiology.

[61]  J. Barker,et al.  Differential and transient expression of GABAA receptor alpha-subunit mRNAs in the developing rat CNS , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[62]  W. Burnham Primary and “Transfer” Seizure Development in the Kindled Rat , 1975, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[63]  I. Leppik Intractable epilepsy in adults. , 1992, Epilepsy research. Supplement.

[64]  Dieter Schmidt,et al.  New horizons in the development of antiepileptic drugs , 2002, Epilepsy Research.

[65]  W. Löscher,et al.  Kindling alters the anticonvulsant efficacy of phenytoin in Wistar rats , 2000, Epilepsy Research.

[66]  Z. Bortolotto,et al.  Long‐Term Effects of Pilocarpine in Rats: Structural Damage of the Brain Triggers Kindling and Spontaneous I Recurrent Seizures , 1991, Epilepsia.

[67]  D. Tauck,et al.  Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[68]  F. Dudek,et al.  Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats , 1988, Brain Research.

[69]  W. Löscher,et al.  Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations , 1988, Epilepsy Research.

[70]  A. Wauquier,et al.  Behavioral analysis of amygdaloid kindling in beagle dogs and the effects of clonazepam, diazepam, phenobarbital, diphenylhydantoin, and flunarizine on seizure manifestation , 1979, Experimental Neurology.

[71]  Jillian H. Fecteau,et al.  Development of spontaneous seizures over extended electrical kindling I. Electrographic, behavioral, and transfer kindling correlates , 1998, Brain Research.

[72]  J. Goodman Experimental Models of Status Epilepticus , 2019, Neuropharmacology Methods in Epilepsy Research.

[73]  I. Módy,et al.  Zinc-Induced Collapse of Augmented Inhibition by GABA in a Temporal Lobe Epilepsy Model , 1996, Science.

[74]  Martin Vreugdenhil,et al.  Effect of valproic acid on sodium currents in cortical neurons from patients with pharmaco-resistant temporal lobe epilepsy , 1998, Epilepsy Research.

[75]  R. S. Sloviter,et al.  Apoptosis and necrosis induced in different hippocampal neuron populations by repetitive perforant path stimulation in the rat , 1996, The Journal of comparative neurology.

[76]  O. Lindvall,et al.  Epileptogenesis induced by rapidly recurring seizures in genetically fast- but not slow-kindling rats , 1998, Brain Research.

[77]  G. V. Goddard,et al.  Transfer, interference and spontaneous recovery of convulsions kindled from the rat amygdala. , 1973, Electroencephalography and clinical neurophysiology.

[78]  R. Racine,et al.  Development of kindling-prone and kindling-resistant rats: selective breeding and electrophysiological studies , 1999, Epilepsy Research.

[79]  R. Palmiter,et al.  Knock-Out Mice Reveal a Critical Antiepileptic Role for Neuropeptide Y , 1997, The Journal of Neuroscience.

[80]  R. Spector Drug Transport in the Mammalian Central Nervous System: Multiple Complex Systems , 2000, Pharmacology.

[81]  D. Mcintyre,et al.  Perirhinal cortex involvement in limbic kindled seizures , 1996, Epilepsy Research.

[82]  J. Pinel Kindling-induced experimental epilepsy in rats: Cortical stimulation , 1981, Experimental Neurology.

[83]  E. Perucca,et al.  A Multicenter Randomized Controlled Trial on the Clinical Impact of Therapeutic Drug Monitoring in Patients with Newly Diagnosed Epilepsy , 2000, Epilepsia.

[84]  C. Elger,et al.  Properties of voltage-activated Ca2+ currents in acutely isolated human hippocampal granule cells. , 1997, Journal of neurophysiology.

[85]  Amygdala lesions and CER learning: long term effect of kindling. , 1972, Physiology & behavior.

[86]  W. Löscher,et al.  Kindling as a model of drug-resistant partial epilepsy: selection of phenytoin-resistant and nonresistant rats. , 1991, The Journal of pharmacology and experimental therapeutics.

[87]  R. S. Sloviter,et al.  The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy , 1994, Annals of neurology.

[88]  D. Schmidt The clinical impact of new antiepileptic drugs after a decade of use in epilepsy , 2002, Epilepsy Research.

[89]  W. Staines,et al.  Efferent projections of the anterior perirhinal cortex in the rat , 1996, The Journal of comparative neurology.

[90]  K. Holloway,et al.  GABAA receptor function in epileptic human dentate granule cells: comparison to epileptic and control rat , 1998, Epilepsy Research.

[91]  D. Mcintyre Split-Brain Rat: Transfer and Interference of Kindled Amygdala Convulsions , 1975, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[92]  J. Gotman,et al.  Relationships between triggered seizures, spontaneous seizures, and interictal spiking in the kindling model of epilepsy , 1984, Experimental Neurology.

[93]  W. Löscher,et al.  Amygdala-kindling as a model for chronic efficacy studies on antiepileptic drugs: Experiments with carbamazepine , 1989, Neuropharmacology.

[94]  J. Eberwine,et al.  Analysis of gene expression in single live neurons. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[95]  D. Mcintyre,et al.  A new model of partial status epilepticus based on kindling , 1982, Brain Research.

[96]  Wolfgang Löscher,et al.  Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. , 2002, The Journal of pharmacology and experimental therapeutics.

[97]  W. Löscher,et al.  Selection of Phenytoin Responders and Nonresponders in Male and Female Amygdala‐Kindled Sprague–Dawley Rats , 1998, Epilepsia.

[98]  R. Wong,et al.  Cellular and synaptic properties of amygdala-kindled pyriform cortex in vitro. , 1986, Journal of neurophysiology.

[99]  W. Löscher Animal Models of Epilepsy and Epileptic Seizures , 1999 .

[100]  The Role of Rhinencephalic Networks in Early Stage Kindling , 1998 .

[101]  J. Cavazos,et al.  Long‐term structural and functional alterations induced in the hippocampus by kindling: Implications for memory dysfunction and the development of epilepsy , 1994, Hippocampus.

[102]  R. Racine,et al.  Rates of motor seizure development in rats subjected to electrical brain stimulation: strain and inter-stimulation interval effects. , 1973, Electroencephalography and clinical neurophysiology.

[103]  C E Elger,et al.  Electrophysiological characterization of Na+ currents in acutely isolated human hippocampal dentate granule cells , 1998, The Journal of physiology.

[104]  C. E. Elger,et al.  Voltage-dependent Ca2+ currents in epilepsy , 1998, Epilepsy Research.

[105]  Carl W. Cotman,et al.  Selective reinnervation of hippocampal area CA1 and the fascia dentata after destruction of CA3-CA4 afferents with kainic acid , 1980, Brain Research.

[106]  W. Löscher,et al.  Characterization of phenytoin-resistant kindled rats, a new model of drug-resistant partial epilepsy: influence of genetic factors , 1999, Epilepsy Research.