Epileptogenicity in the Developing Brain

Summary

Principal Investigator: RAMAN R SANKAR
Abstract: Children with epilepsy have more cognitive and psychiatric difficulties than children with other chronic illnesses. Pediatric neurologists are acutely aware of the distinctive manner in which the immature brain responds differently to a variety of insults as well as to therapeutic interventions. In March of 2000, NINDS coordinated a White House-initiated conference on "Curing Epilepsy" that identified interrupting the process of epileptogenesis as the number one agenda. The need for discovering the range of anatomic, physiological, and molecular substrates associated with the epilepsies and defining unambiguous markers of epileptogenicity was set as a major priority at that conference. The research proposed here has two goals, linked by the theme of the consequences of seizures on the developing brain. Specifically, this study will focus on (1) seizure-induced brain injury, and (2) the resulting alterations in structure and function of the developing brain that are epileptogenic. In studying seizure induced brain injury, the proposed work aims to determine the influence of (a) the developmental stage of the animals and (b) the duration of status epilepticus, that may constitute a threshold for injury. Mechanisms of cell-death (necrotic versus programmed cell death) will be studied as a function of these variables. The study will seek to isolate distinct processes critical in producing neuronal injury that may become evident during the course of status epilepticus. Animals will be observed over several months for the development of chronic spontaneous seizures, i.e. epilepsy, after the initial bout of status epilepticus, in order to determine the threshold duration of status epilepticus that is epileptogenic, and how this is modified by the developmental stage of the brain. These animals will be studied for anatomic (evidence of mossy fiber sprouting in the hippocampus) and physiologic (population spike amplitude and EPSP slope) alterations that accompany the onset and progression of epilepsy after a bout of status epilepticus during development. Our findings will provide the basis for future neuroprotective interventions targeting the developing brain at different stages of status epilepticus in order to interrupt the course of the epileptogenic process.
Funding Period: 2004-02-01 - 2010-01-31
more information: NIH RePORT

Top Publications

  1. pmc Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy
    Andrey M Mazarati
    Department of Pediatrics, Neurology Division, David Geffen School of Medicine, University of California Los Angeles, Box 951752, 22 474 MDCC, Los Angeles, CA 90095 1752, USA
    Neurobiol Dis 34:457-61. 2009
  2. pmc Evaluation of development-specific targets for antiepileptogenic therapy using rapid kindling
    Raman Sankar
    Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
    Epilepsia 51:39-42. 2010
  3. pmc Hypoxic-ischemic brain injury exacerbates neuronal apoptosis and precipitates spontaneous seizures in glucose transporter isoform 3 heterozygous null mice
    Camille Fung
    Division of Neonatology and Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, California, USA
    J Neurosci Res 88:3386-98. 2010
  4. pmc Noninvasive testing, early surgery, and seizure freedom in tuberous sclerosis complex
    J Y Wu
    Division of Pediatric Neurology, Mattel Children s Hospital at UCLA, David Geffen School of Medicine, Los Angeles, CA 90095 1752, USA
    Neurology 74:392-8. 2010
  5. ncbi Inflammation modifies status epilepticus-induced hippocampal injury during development
    Raman Sankar
    Department of Pediatrics, David Geffen School of Medicine and Mattel Children s Hospital at UCLA, Los Angeles, California 90095 1752, USA
    Epilepsia 48:16-8. 2007
  6. pmc Antiepileptogenic and antiictogenic effects of retigabine under conditions of rapid kindling: an ontogenic study
    Andrey Mazarati
    Department of Pediatrics, Neurology Division, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 1752, USA
    Epilepsia 49:1777-86. 2008
  7. pmc Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine
    Andrey Mazarati
    Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1752, USA
    Brain 131:2071-83. 2008
  8. ncbi Paroxysmal fast activity: an interictal scalp EEG marker of epileptogenesis in children
    Joyce Y Wu
    Division of Pediatric Neurology, Mattel Children s Hospital at UCLA, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States
    Epilepsy Res 82:99-106. 2008
  9. pmc Bumetanide inhibits rapid kindling in neonatal rats
    Andrey Mazarati
    Department of Pediatrics, Neurology Division, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 1752, USA
    Epilepsia 50:2117-22. 2009
  10. pmc Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders
    Y Zhao
    Division of Neonatology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, CA 90095, USA
    Mol Psychiatry 15:286-99. 2010

Scientific Experts

Detail Information

Publications26

  1. pmc Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy
    Andrey M Mazarati
    Department of Pediatrics, Neurology Division, David Geffen School of Medicine, University of California Los Angeles, Box 951752, 22 474 MDCC, Los Angeles, CA 90095 1752, USA
    Neurobiol Dis 34:457-61. 2009
    ..We suggest that the observed hyperactivity of the HPA axis may underlie co-morbidity between epilepsy and depression...
  2. pmc Evaluation of development-specific targets for antiepileptogenic therapy using rapid kindling
    Raman Sankar
    Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
    Epilepsia 51:39-42. 2010
    ..Although the utility of this model for screening the antiepileptogenic therapies requires further validation, it introduces the ability to undertake development-specific testing and a more rapid throughput than conventional methods...
  3. pmc Hypoxic-ischemic brain injury exacerbates neuronal apoptosis and precipitates spontaneous seizures in glucose transporter isoform 3 heterozygous null mice
    Camille Fung
    Division of Neonatology and Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, California, USA
    J Neurosci Res 88:3386-98. 2010
    ..WT mice, with no detectable differences in monamine neurotransmitters. We conclude that hypoxic-ischemic brain injury in glut3(+/-) mice exacerbates cellular apoptosis and necrosis and precipitates spontaneous seizures...
  4. pmc Noninvasive testing, early surgery, and seizure freedom in tuberous sclerosis complex
    J Y Wu
    Division of Pediatric Neurology, Mattel Children s Hospital at UCLA, David Geffen School of Medicine, Los Angeles, CA 90095 1752, USA
    Neurology 74:392-8. 2010
    ..We assessed whether magnetic source imaging (MSI) and coregistration of (18)fluorodeoxyglucose PET (FDG-PET) with MRI could improve the identification of the epileptogenic regions noninvasively in children with TSC...
  5. ncbi Inflammation modifies status epilepticus-induced hippocampal injury during development
    Raman Sankar
    Department of Pediatrics, David Geffen School of Medicine and Mattel Children s Hospital at UCLA, Los Angeles, California 90095 1752, USA
    Epilepsia 48:16-8. 2007
  6. pmc Antiepileptogenic and antiictogenic effects of retigabine under conditions of rapid kindling: an ontogenic study
    Andrey Mazarati
    Department of Pediatrics, Neurology Division, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 1752, USA
    Epilepsia 49:1777-86. 2008
    ..To examine antiepileptogenic and antiictogenic potential of retigabine (RTG) under conditions of rapid kindling epileptogenesis during different stages of development...
  7. pmc Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine
    Andrey Mazarati
    Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1752, USA
    Brain 131:2071-83. 2008
    ..The finding that behavioural equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways...
  8. ncbi Paroxysmal fast activity: an interictal scalp EEG marker of epileptogenesis in children
    Joyce Y Wu
    Division of Pediatric Neurology, Mattel Children s Hospital at UCLA, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States
    Epilepsy Res 82:99-106. 2008
    ..This study explored if beta- and gamma-frequency paroxysmal fast activity (PFA), recorded interictally during non-REM sleep, could be used as a scalp EEG marker of epileptogenesis in children...
  9. pmc Bumetanide inhibits rapid kindling in neonatal rats
    Andrey Mazarati
    Department of Pediatrics, Neurology Division, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 1752, USA
    Epilepsia 50:2117-22. 2009
    ..To examine the effects of bumetanide, a selective blocker of Na+-K+-2Cl- cotransporter (NKCC1), on hippocampal excitability and rapid kindling in immature rats...
  10. pmc Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders
    Y Zhao
    Division of Neonatology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, CA 90095, USA
    Mol Psychiatry 15:286-99. 2010
    ..This is the first description of GLUT3 deficiency that forms a possible novel genetic mechanism for pervasive developmental disorders, such as the neuropsychiatric autism spectrum disorders, requiring further investigation in humans...
  11. pmc Acute neuroprotection to pilocarpine-induced seizures is not sustained after traumatic brain injury in the developing rat
    G G Gurkoff
    Department of Neurosurgery, David Geffen School of Medicine at University of California Los Angeles, 10833 Le Conte Avenue, 18 228 Semel Institute, Los Angeles, CA 90095 7039, USA
    Neuroscience 164:862-76. 2009
    ....
  12. ncbi Inflammation exacerbates seizure-induced injury in the immature brain
    St├ęphane Auvin
    Department of Pediatrics, Division of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
    Epilepsia 48:27-34. 2007
    ....
  13. ncbi Inflammation contributes to seizure-induced hippocampal injury in the neonatal rat brain
    R Sankar
    Division of Neurology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Mattel Children s Hospital at UCLA, Los Angeles, CA 90095, USA
    Acta Neurol Scand Suppl 186:16-20. 2007
    ..Neonatal seizures often occur in clinical settings that include an inflammatory component. We examined the potential contributory role of pre-existing inflammation as an important variable in mediating neuronal injury...
  14. ncbi Status epilepticus and frequent seizures: incidence and clinical characteristics in pediatric epilepsy surgery patients
    Susan Koh
    Division of Pediatric Neurology, UCLA Medical Center, Los Angeles, CA 90095, USA
    Epilepsia 46:1950-4. 2005
    ..However, this concept is based on case reports, and the incidence and clinical characteristics of these patients have not been systematically assessed...
  15. ncbi Treatment of experimental status epilepticus in immature rats: dissociation between anticonvulsant and antiepileptogenic effects
    Lucie Suchomelova
    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 90095, USA
    Pediatr Res 59:237-43. 2006
    ..Diazepam, on the other hand, was a better anticonvulsant than an antiepileptogenic agent in the P15 animals at the dose tested. Such effects were not seen in the older animals...
  16. ncbi Magnetic source imaging localizes epileptogenic zone in children with tuberous sclerosis complex
    J Y Wu
    Division of Pediatric Neurology, The Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
    Neurology 66:1270-2. 2006
    ..02), whereas interictal MEG/MSI fared better (100%, 94%, and 95%, respectively; p < 0.0001). Interictal MEG/MSI seems to identify epileptogenic zones more accurately in children with TSC and focal intractable epilepsy...
  17. pmc Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors: The effects of subtype-selective agonists and the role of G-protein-mediated signaling
    Andrey Mazarati
    Department of Pediatrics, Division of Pediatric Neurology, D Geffen School of Medicine at UCLA, Box 951752, 22 474 MDCC, Los Angeles, CA 90095 1752, USA
    J Pharmacol Exp Ther 318:700-8. 2006
    ..The data are important for understanding endogenous mechanisms regulating epileptogenesis and for the development of novel antiepileptogenic drugs...
  18. ncbi Children with ESES: variability in the syndrome
    Michele Van Hirtum-Das
    Department of Pediatrics and Neurology, David Geffen School of Medicine at UCLA, Mattel Children s Hospital at UCLA, Los Angeles, CA, USA
    Epilepsy Res 70:S248-58. 2006
    ..We undertook a retrospective study of children who present with significant activation of paroxysmal discharges during sleep to examine the clinical spectrum of disorders that present with such an EEG abnormality...
  19. pmc Age-dependent effects of topiramate on the acquisition and the retention of rapid kindling
    Andrey Mazarati
    Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1752, USA
    Epilepsia 48:765-73. 2007
    ..To examine antiepileptogenic, disease modifying, and anticonvulsant effects of topiramate under conditions of rapid kindling at different stages of development...
  20. ncbi Inflammation contributes to seizure-induced hippocampal injury in the neonatal rat brain
    R Sankar
    Division of Neurology, Department of Pediatrics, David Geffen School of Medicine at UCLA and Mattel Children s Hospital at UCLA, Los Angeles, CA 90095, USA
    Acta Neurol Scand 115:16-20. 2007
    ..Neonatal seizures often occur in clinical settings that include an inflammatory component. We examined the potential contributory role of pre-existing inflammation as an important variable in mediating neuronal injury...
  21. pmc Kindling epileptogenesis in immature rats leads to persistent depressive behavior
    Andrey Mazarati
    Department of Pediatrics, David Geffen School of Medicine at UCLA, Room 22 474 MDCC, Los Angeles, CA 90095 1752, USA
    Epilepsy Behav 10:377-83. 2007
    ..We conclude that neuronal plastic changes associated with the kindling state are accompanied by the development of depressive behavior...
  22. ncbi Status epilepticus triggers caspase-3 activation and necrosis in the immature rat brain
    Jerome Niquet
    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
    Epilepsia 48:1203-6. 2007
    ..Caspase-3 was activated in injured (acidophilic) neurons 24 hours following SE, raising the possibility that they died by caspase-dependent "programmed" necrosis...
  23. ncbi Teratogenicity of antiepileptic drugs: role of drug metabolism and pharmacogenomics
    R Sankar
    David Geffen School of Medicine and Mattel Children s Hospital, UCLA, Los Angeles, CA 90095 1752, USA
    Acta Neurol Scand 116:65-71. 2007
    ....
  24. ncbi Do seizures affect the developing brain? Lessons from the laboratory
    Raman Sankar
    David Geffen School of Medicine, UCLA, Los Angeles, California, USA
    J Child Neurol 22:21S-9S. 2007
    ..For now, prevention of prolonged seizures with early intervention is important and is the most effective available option to minimize the potential short- and long-term adverse effects of prolonged seizures and optimize patient outcomes...
  25. pmc In vivo interaction between serotonin and galanin receptors types 1 and 2 in the dorsal raphe: implication for limbic seizures
    Andrey M Mazarati
    Department of Pediatrics, Division of Pediatric Neurology, D Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
    J Neurochem 95:1495-503. 2005
    ....