Status epilepticus-induced pathologic plasticity in a rat model of focal cortical dysplasia.

We have generated an experimental 'double-hit' model of chronic epilepsy to recapitulate the co-existence of abnormal cortical structure and frequently recurrent seizures as observed in human focal cortical dysplasia. We induced cortical malformations by exposing rats prenatally to methylazoxymethanol acetate and triggered status epilepticus and recurrent seizures in adult methylazoxymethanol acetate rats with pilocarpine. We studied the course of epilepsy and the long-term morphologic and molecular changes induced by the occurrence of status epilepticus and subsequent chronic epilepsy in the malformed methylazoxymethanol acetate exposed brain. Behavioural and electroencephalographic analyses showed that methylazoxymethanol acetate pilocarpine rats develop more severe epilepsy than naïve rats. Morphologic and molecular analyses demonstrated that status epilepticus and subsequent seizures, but not pilocarpine treatment per se, was capable of affecting both cortical architectural and N-methyl-D-aspartate receptor abnormalities induced by methylazoxymethanol acetate. In particular, cortical thickness was further decreased and N-methyl-D-aspartate regulatory subunits were recruited at the postsynaptic membrane. In addition, methylazoxymethanol acetate pilocarpine rats showed abnormally large cortical pyramidal neurons with neurofilament over-expression. These neurons bear similarities to the hypertrophic/dysmorphic pyramidal neurons observed in acquired human focal cortical dysplasia. These data show that status epilepticus sets in motion a pathological process capable of significantly changing the cellular and molecular features of pre-existing experimental cortical malformations. They suggest that seizure recurrence in human focal cortical dysplasia might be an additional factor in establishing a pathological circuitry that favours chronic neuronal hyperexcitability.

[1]  P. Schwartzkroin,et al.  Electrophysiology of CA1 pyramidal neurons in an animal model of neuronal migration disorders: prenatal methylazoxymethanol treatment , 1995, Epilepsy Research.

[2]  H. Shigeto,et al.  Prenatal freeze lesioning produces epileptogenic focal cortical dysplasia , 2008, Epilepsia.

[3]  S. Moshé,et al.  Evidence of Enhanced Kindliig and Hippocampal Neuronal Injury in Immature Rats with Neuronal Migration Disorders , 1998, Epilepsia.

[4]  J. González-Martínez,et al.  The NMDA receptor NR2B subunit contributes to epileptogenesis in human cortical dysplasia , 2005, Brain Research.

[5]  E. Schönau.  The Development of the Skeletal System in Children and the Influence of Muscular Strength , 1997, Hormone Research in Paediatrics.

[6]  F Andermann,et al.  Focal neuronal migration disorders and intractable partial epilepsy: Results of surgical treatment , 1991, Annals of neurology.

[7]  Itzhak Fried,et al.  Assessment and surgical outcomes for mild type I and severe type II cortical dysplasia: A critical review and the UCLA experience , 2009, Epilepsia.

[8]  M. di Luca,et al.  The NMDA Receptor Complex Is Altered in an Animal Model of Human Cerebral Heterotopia , 2003, Journal of neuropathology and experimental neurology.

[9]  Maria Thom,et al.  The clinicopathologic spectrum of focal cortical dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission 1 , 2011, Epilepsia.

[10]  L. Swanson.  The Rat Brain in Stereotaxic Coordinates, George Paxinos, Charles Watson (Eds.). Academic Press, San Diego, CA (1982), vii + 153, $35.00, ISBN: 0 125 47620 5 , 1984 .

[11]  R. C. Collins,et al.  The functional anatomy and pathology of lithium-pilocarpine and high-dose pilocarpine seizures , 1987, Neuroscience.

[12]  P. Calabresi,et al.  Decreased NR2B Subunit Synaptic Levels Cause Impaired Long-Term Potentiation But Not Long-Term Depression , 2009, The Journal of Neuroscience.

[13]  J. Winn,et al.  Brain , 1878, The Lancet.

[14]  L. Tassi,et al.  NMDA Receptor Composition Differs Among Anatomically Diverse Malformations of Cortical Development , 2006, Journal of neuropathology and experimental neurology.

[15]  I. Choi,et al.  Pilocarpine-induced seizure susceptibility in rats following prenatal methylazoxymethanol treatment. , 2005, Biological & pharmaceutical bulletin.

[16]  A. Vercelli,et al.  Experimentally-induced microencephaly: effects on cortical neurons , 2003, Brain Research Bulletin.

[17]  F Andermann,et al.  Focal neuronal migration disorders and intractable partial epilepsy: A study of 30 patients , 1991, Annals of neurology.

[18]  Yingming Zhao,et al.  The Presynaptic Particle Web Ultrastructure, Composition, Dissolution, and Reconstitution , 2001, Neuron.

[19]  G. Battaglia,et al.  CHAPTER 23 – MAM and Other “Lesion” Models of Developmental Epilepsy , 2006 .

[20]  I. Scheffer,et al.  Clinical and imaging heterogeneity of polymicrogyria: a study of 328 patients. , 2010, Brain : a journal of neurology.

[21]  G. Battaglia,et al.  The genesis of epileptogenic cerebral heterotopia: clues from experimental models. , 2003, Epileptic disorders : international epilepsy journal with videotape.

[22]  G. Avanzini,et al.  Prenatal methylazoxymethanol treatment in rats produces brain abnormalities with morphological similarities to human developmental brain dysgeneses. , 1999, Journal of neuropathology and experimental neurology.

[23]  Ludovico D'Incerti,et al.  Periventricular Nodular Heterotopia: Classification, Epileptic History, and Genesis of Epileptic Discharges , 2006, Epilepsia.

[24]  T. Babb,et al.  Epileptogenicity Correlated with Increased N‐Methyl‐d‐Aspartate Receptor Subunit NR2A/B in Human Focal Cortical Dysplasia , 2000, Epilepsia.

[25]  H. Scharfman,et al.  The Influence of Gonadal Hormones on Neuronal Excitability, Seizures, and Epilepsy in the Female , 2006, Epilepsia.

[26]  L F Quesney,et al.  Usefulness of focal rhythmic discharges on scalp EEG of patients with focal cortical dysplasia and intractable epilepsy. , 1996, Electroencephalography and clinical neurophysiology.

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

[28]  J. Parisi,et al.  Shaken infant syndrome: developmental neuropathology, progressive cortical dysplasia, and epilepsy , 2002, Acta Neuropathologica.

[29]  M A Falconer,et al.  Focal dysplasia of the cerebral cortex in epilepsy , 1971, Journal of neurology, neurosurgery, and psychiatry.

[30]  T. Babb,et al.  Induced Expression of NMDAR2 Proteins and Differential Expression of NMDAR1 Splice Variants in Dysplastic Neurons of Human Epileptic Neocortex , 1998, Journal of neuropathology and experimental neurology.

[31]  Y. Ben-Ari,et al.  Neuronal migration disorders: heterotopic neocortical neurons in CA1 provide a bridge between the hippocampus and the neocortex. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Y. Ben-Ari,et al.  Neocortex in the hippocampus: An anatomical and functional study of CA1 heterotopias after prenatal treatment with methylazoxymethanol in rats , 1998, The Journal of comparative neurology.

[33]  Y. Ben-Ari,et al.  Decreased seizure threshold and more rapid rate of kindling in rats with cortical malformation induced by prenatal treatment with methylazoxymethanol. , 1998, Brain Research.

[34]  P. Schwartzkroin,et al.  Characterization of heterotopic cell clusters in the hippocampus of rats exposed to methylazoxymethanol in utero , 2000, Epilepsy Research.

[35]  A. J. Barkovich,et al.  Classification system for malformations of cortical development , 2001, Neurology.

[36]  J. Henley,et al.  Ultrastructural localisation and differential agonist‐induced regulation of AMPA and kainate receptors present at the presynaptic active zone and postsynaptic density , 2006, Journal of neurochemistry.

[37]  S. Roper,et al.  Altered Corticogenesis and Neuronal Morphology in Irradiation‐Induced Cortical Dysplasia: A Golgi‐Cox Study , 2003, Journal of neuropathology and experimental neurology.

[38]  J. DeFelipe,et al.  Microanatomy of the dysplastic neocortex from epileptic patients. , 2004, Brain : a journal of neurology.

[39]  M. Luca,et al.  Dysplastic neocortex and subcortical heterotopias in methylazoxymethanol-treated rats: an intracellular study of identified pyramidal neurones , 1998, Neuroscience Letters.

[40]  R. Neumar,et al.  Selective Activation Induced Cleavage of the NR2B Subunit by Calpain , 2003, The Journal of Neuroscience.

[41]  B. Fritsch,et al.  Treatment of early and late kainic acid‐induced status epilepticus with the noncompetitive AMPA receptor antagonist GYKI 52466 , 2010, Epilepsia.

[42]  H. Scharfman,et al.  A rat model of epilepsy in women: a tool to study physiological interactions between endocrine systems and seizures. , 2009, Endocrinology.

[43]  N. Boddaert,et al.  LIS1-related isolated lissencephaly: spectrum of mutations and relationships with malformation severity. , 2009, Archives of neurology.

[44]  C. Cepeda,et al.  Human cortical dysplasia and epilepsy: an ontogenetic hypothesis based on volumetric MRI and NeuN neuronal density and size measurements. , 2004, Cerebral cortex.

[45]  B. Sakmann,et al.  Developmental and regional expression in the rat brain and functional properties of four NMDA receptors , 1994, Neuron.

[46]  I. Najm,et al.  Pathophysiological Mechanisms of Focal Cortical Dysplasia: A Critical Review of Human Tissue Studies and Animal Models , 2007, Epilepsia.

[47]  Asla Pitkänen,et al.  Models of Seizures and Epilepsy , 2005 .

[48]  J. Gurd,et al.  Increase in tyrosine phosphorylation of the NMDA receptor following the induction of status epilepticus , 2006, Neuroscience Letters.

[49]  L Tassi,et al.  Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. , 2002, Brain : a journal of neurology.

[50]  Zhen Yan,et al.  Postsynaptic Density-95 (PSD-95) and Calcineurin Control the Sensitivity of N-Methyl-d-aspartate Receptors to Calpain Cleavage in Cortical Neurons , 2008, Molecular Pharmacology.

[51]  M. Calcagnotto,et al.  Prolonged NMDA-mediated responses, altered ifenprodil sensitivity, and epileptiform-like events in the malformed hippocampus of methylazoxymethanol exposed rats. , 2005, Journal of neurophysiology.

[52]  F. Dudek,et al.  Epileptogenesis in the dentate gyrus: a critical perspective. , 2007, Progress in brain research.

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

[54]  G. Ricci,et al.  Seizure susceptibility in immature rats with micrencephaly induced by prenatal exposure to methylazoxymethanol acetate. , 1995, Pharmacological research.

[55]  C. Cepeda,et al.  NMDA receptor alterations in neurons from pediatric cortical dysplasia tissue. , 2004, Cerebral cortex.

[56]  C. Cepeda,et al.  Are Cytomegalic Neurons and Balloon Cells Generators of Epileptic Activity in Pediatric Cortical Dysplasia? , 2005, Epilepsia.

[57]  Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia , 2001 .

[58]  P. Crino,et al.  Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia , 2001, Neurology.

[59]  F. Pontén,et al.  DLG3/SAP102 protein expression in malformations of cortical development: A study of human epileptic cortex by tissue microarray , 2009, Epilepsy Research.

[60]  Maria Thom,et al.  Malformations of cortical development and epilepsies: neuropathological findings with emphasis on focal cortical dysplasia. , 2009, Epileptic disorders : international epilepsy journal with videotape.

[61]  M. di Luca,et al.  Neurogenesis in cerebral heterotopia induced in rats by prenatal methylazoxymethanol treatment. , 2003, Cerebral cortex.

[62]  T. Babb,et al.  Selective Coexpression of NMDAR2A/B and NMDAR1 Subunit Proteins in Dysplastic Neurons of Human Epileptic Cortex , 1999, Experimental Neurology.

[63]  I. Najm,et al.  Altered Glutamate Receptor—Transporter Expression and Spontaneous Seizures in Rats Exposed to Methylazoxymethanol in Utero , 2007, Epilepsia.

[64]  Andreas Schulze-Bonhage,et al.  Focal cortical dysplasias: surgical outcome in 67 patients in relation to histological subtypes and dual pathology. , 2004, Brain : a journal of neurology.

[65]  J. Pinel,et al.  Electrode placement and kindling-induced experiemental epilepsy , 1978, Experimental Neurology.

[66]  Y. Ben-Ari,et al.  Abnormal Connections in the Malformed Cortex of Rats with Prenatal Treatment with Methylazoxymethanol May Support Hyperexcitability , 1999, Developmental Neuroscience.

[67]  T. Babb,et al.  NMDA‐Receptors 1 and 2A/B Coassembly Increased in Human Epileptic Focal Cortical Dysplasia , 1999, Epilepsia.

[68]  M Marín-Padilla,et al.  Developmental neuropathology and impact of perinatal brain damage. III: gray matter lesions of the neocortex. , 1997, Journal of neuropathology and experimental neurology.

[69]  Frederick Andermann,et al.  Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results , 1995, Annals of neurology.