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Neurotoxicity Research

, Volume 34, Issue 3, pp 511–524 | Cite as

Full Protection Against Soman-Induced Seizures and Brain Damage by LY293558 and Caramiphen Combination Treatment in Adult Rats

  • James P. Apland
  • Vassiliki Aroniadou-Anderjaska
  • Taiza H. Figueiredo
  • Marcio De Araujo Furtado
  • Maria F. M. Braga
ORIGINAL ARTICLE
  • 62 Downloads

Abstract

Acute exposure to nerve agents induces status epilepticus (SE), which causes brain damage or death. LY293558, an antagonist of AMPA and GluK1 kainate receptors is a very effective anticonvulsant and neuroprotectant against soman; however, some neuronal damage is still present after treatment of soman-exposed rats with LY293558. Here, we have tested whether combining LY293558 with an NMDA receptor antagonist can eliminate the residual damage. For this purpose, we chose caramiphen (CRM), an antimuscarinic compound with NMDA receptor antagonistic properties. Adult male rats were exposed to 1.2 × LD50 soman, and at 20 min after soman exposure, were injected with atropine + HI-6, or atropine + HI-6 + LY293558 (15 mg/kg), or atropine + HI-6 + LY293558 + CRM (50 mg/kg). We found that (1) the LY293558 + CRM treatment terminated SE significantly faster than LY293558 alone; (2) after cessation of the initial SE, seizures did not return in the LY293558 + CRM-treated group, during 72 h of monitoring; (3) power spectrum analysis of continuous EEG recordings for 7 days post-exposure showed increased delta and decreased gamma power that lasted beyond 24 h post-exposure only in the rats who did not receive anticonvulsant treatment; (4) spontaneous recurrent seizures appeared on day 7 only in the group that did not receive anticonvulsant treatment; (5) significant neuroprotection was achieved by LY293558 administration, while the rats who received LY293558 + CRM displayed no neurodegeneration; (6) body weight loss and recovery in the LY293558 + CRM-treated rats did not differ from those in control rats who were not exposed to soman. The data show that treatment with LY293558 + CRM provides full antiseizure and neuroprotective efficacy against soman.

Keywords

Nerve agents Status epilepticus AMPA receptors GluK1-kainate receptors NMDA receptors Caramiphen 

Notes

Funding Information

This research was supported by the CounterACT Program, National Institutes of Health, Office of the Director and the National Institute of Neurologic Disorders and Stroke [Grant Number 5U01NS058162-07].

Compliance with Ethical Standards

Conflict of Interest Statement

The authors declare that they have no conflict of interest.

References

  1. Allen K, Monyer H (2015) Interneuron control of hippocampal oscillations. Curr Opin Neurobiol 31:81–87CrossRefGoogle Scholar
  2. Annels SJ, Ellis Y, Davies JA (1991) Non-opioid antitussives inhibit endogenous glutamate release from rabbit hippocampal slices. Brain Res 564:341–343CrossRefGoogle Scholar
  3. Apland JP, Figueiredo TH, Qashu F, Aroniadou-Anderjaska V, Souza AP, Braga MF (2010) Higher susceptibility of the ventral versus the dorsal hippocampus and the posteroventral versus anterodorsal amygdala to soman-induced neuropathology. Neurotoxicology 31:485–492CrossRefGoogle Scholar
  4. Apland JP, Aroniadou-Anderjaska V, Figueiredo TH, Green CE, Swezey R, Yang C, Qashu F, Braga MF (2013) Efficacy of the GluK1/AMPA receptor antagonist LY293558 against seizures and neuropathology in a soman-exposure model without pretreatment and its pharmacokinetics after intramuscular administration. J Pharmacol Exp Ther 344:133–140CrossRefGoogle Scholar
  5. Apland JP, Aroniadou-Anderjaska V, Figueiredo TH, Rossetti F, Miller SL, Braga MF (2014) The limitations of diazepam as a treatment for nerve agent-induced seizures and neuropathology in rats: comparison with UBP302. J Pharmacol Exp Ther 351:359–372CrossRefGoogle Scholar
  6. Apland JP, Aroniadou-Anderjaska V, Figueiredo TH, Prager EM, Olsen CH, Braga MFM (2017) Susceptibility to soman toxicity and efficacy of LY293558 against soman-induced seizures and neuropathology in 10-month-old male rats. Neurotox Res 32:694–706CrossRefGoogle Scholar
  7. Apland JP, Aroniadou-Anderjaska V, Figueiredo TH, Pidoplichko VI, Rossetti K, Braga MFM (2018) Comparing the antiseizure and neuroprotective efficacy of LY293558, diazepam, caramiphen, and LY293558-caramiphen combination against soman in a rat model relevant to the pediatric population. J Pharmacol Exp Ther 365:314–326Google Scholar
  8. Aroniadou-Anderjaska V, Fritsch B, Qashu F, Braga MF (2008) Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy. Epilepsy Res 78:102–116CrossRefGoogle Scholar
  9. Aroniadou-Anderjaska V, Figueiredo TH, Apland JP, Qashu F, Braga MF (2009) Primary brain targets of nerve agents: the role of the amygdala in comparison to the hippocampus. Neurotoxicology 30:772–776CrossRefGoogle Scholar
  10. Aroniadou-Anderjaska V, Figueiredo TH, Apland JP, Prager EM, Pidoplichko VI, Miller SL, Braga MF (2016) Long-term neuropathological and behavioral impairments after exposure to nerve agents. Ann N Y Acad Sci 1374:17–28CrossRefGoogle Scholar
  11. Aroniadou-Anderjaska V, Pidoplichko VI, Figueiredo TH, Braga MFM (2018) Oscillatory synchronous inhibition in the basolateral amygdala and its primary dependence on NR2A-containing NMDA receptors. Neuroscience 373:145–158CrossRefGoogle Scholar
  12. Bleakman R, Schoepp DD, Ballyk B, Bufton H, Sharpe EF, Thomas K, Ornstein PL, Kamboj RK (1996) Pharmacological discrimination of GluR5 and GluR6 kainate receptor subtypes by (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahyd roisdoquinoline-3 carboxylic-acid. Mol Pharmacol 49:581–585PubMedGoogle Scholar
  13. Campo-Soria C, Chang Y, Weiss DS (2006) Mechanism of action of benzodiazepines on GABAA receptors. Br J Pharmacol 148:984–990CrossRefGoogle Scholar
  14. Carpentier P, Foquin A, Rondouin G, Lerner-Natoli M, de Groot DM, Lallement G (2000) Effects of atropine sulphate on seizure activity and brain damage produced by soman in guinea-pigs: ECoG correlates of neuropathology. Neurotoxicology 21:521–540PubMedGoogle Scholar
  15. Carpentier P, Foquin A, Dorandeu F, Lallement G (2001) Delta activity as an early indicator for soman-induced brain damage: a review. Neurotoxicology 22:299–315CrossRefGoogle Scholar
  16. Cherian A, Thomas SV (2009) Status epilepticus. Ann Indian Acad Neurol 12:140–153CrossRefGoogle Scholar
  17. Church J, Fletcher EJ (1995) Blockade by sigma site ligands of high voltage-activated Ca2+ channels in rat and mouse cultured hippocampal pyramidal neurones. Br J Pharmacol 116:2801–2810CrossRefGoogle Scholar
  18. de Araujo FM, Zheng A, Sedigh-Sarvestani M, Lumley L, Lichtenstein S, Yourick D (2009) Analyzing large data sets acquired through telemetry from rats exposed to organophosphorous compounds: an EEG study. J Neurosci Methods 184:176–183CrossRefGoogle Scholar
  19. De Araujo FM, Lumley LA, Robison C, Tong LC, Lichtenstein S, Yourick DL (2010) Spontaneous recurrent seizures after status epilepticus induced by soman in Sprague-Dawley rats. Epilepsia 51:1503–1510CrossRefGoogle Scholar
  20. Deeb TZ, Maguire J, Moss SJ (2012) Possible alterations in GABA(a) receptor signaling that underlie benzodiazepine-resistant seizures. Epilepsia 53:79–88CrossRefGoogle Scholar
  21. Deshpande LS, Carter DS, Phillips KF, Blair RE, DeLorenzo RJ (2014) Development of status epilepticus, sustained calcium elevations and neuronal injury in a rat survival model of lethal paraoxon intoxication. Neurotoxicology 44:17–26CrossRefGoogle Scholar
  22. Faught E, Kuzniecky RI, Hurst DC (1992) Ictal EEG wave forms from epidural electrodes predictive of seizure control after temporal lobectomy. Electroencephalogr Clin Neurophysiol 83:229–235CrossRefGoogle Scholar
  23. Fernández T, Herrera W, Harmony T, Díaz-Comas L, Santiago E, Sánchez L, Bosch J, Fernández-Bouzas A, Otero G, Ricardo-Garcell J, Barraza C, Aubert E, Galán L, Valdés R (2003) EEG and behavioral changes following neurofeedback treatment in learning disabled children. Clin Electroencephalogr 34:145–152CrossRefGoogle Scholar
  24. Figueiredo TH, Aroniadou-Anderjaska V, Qashu F, Apland JP, Pidoplichko V, Stevens D, Ferrara TM, Braga MF (2011a) Neuroprotective efficacy of caramiphen against soman and mechanisms of its action. Br J Pharmacol 164:1495–1505CrossRefGoogle Scholar
  25. Figueiredo TH, Aroniadou-Anderjaska V, Qashu F, Apland JP, Pidoplichko V, Stevens D, Ferrara TM, Braga MF (2011b) Neuroprotective efficacy of caramiphen against soman and mechanisms of its action. Br J Pharmacol 164:1495–1505CrossRefGoogle Scholar
  26. Figueiredo TH, Qashu F, Apland JP, Aroniadou-Anderjaska V, Souza AP, Braga MF (2011c) The GluK1 (GluR5) Kainate/{alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 reduces soman-induced seizures and neuropathology. J Pharmacol Exp Ther 336:303–312CrossRefGoogle Scholar
  27. Fletcher EJ, Church J, Abdel-Hamid K, MacDonald JF (1995) Blockade by sigma site ligands of N-methyl-D-aspartate-evoked responses in rat and mouse cultured hippocampal pyramidal neurons. Br J Pharmacol 116:2791–2800CrossRefGoogle Scholar
  28. Fujikawa DG (2015) The role of excitotoxic programmed necrosis in acute brain injury. Comput Struct Biotechnol J 13:212–221CrossRefGoogle Scholar
  29. Gielen MC, Lumb MJ, Smart TG (2012) Benzodiazepines modulate GABAA receptors by regulating the preactivation step after GABA binding. J Neurosci 32:5707–5715CrossRefGoogle Scholar
  30. Goodkin HP, Yeh JL, Kapur J (2005) Status epilepticus increases the intracellular accumulation of GABAA receptors. J Neurosci 25:5511–5520CrossRefGoogle Scholar
  31. Hudkins RL, DeHaven-Hudkins DL (1991) M1 muscarinic antagonists interact with sigma recognition sites. Life Sci 49:1229–1235CrossRefGoogle Scholar
  32. Hudkins RL, Stubbins JF, DeHaven-Hudkins DL (1993) Caramiphen, iodocaramiphen and nitrocaramiphen are potent, competitive, muscarinic M1 receptor-selective agents. Eur J Pharmacol 231:485–488CrossRefGoogle Scholar
  33. Jalilifar M, Yadollahpour A, Moazedi AA, Ghotbeddin Z (2016) Classifying amygdala kindling stages using quantitative assessments of extracellular recording of EEG in rats. Brain Res Bull 127:148–155CrossRefGoogle Scholar
  34. Jane DE, Lodge D, Collingridge GL (2009) Kainate receptors: pharmacology, function and therapeutic potential. Neuropharmacology 56:90–113CrossRefGoogle Scholar
  35. Joseph DJ, Williams DJ, MacDermott AB (2011) Modulation of neurite outgrowth by activation of calcium-permeable kainate receptors expressed by rat nociceptive-like dorsal root ganglion neurons. Dev Neurobiol 71:818–835CrossRefGoogle Scholar
  36. Kemp B, Olivan J (2003) European data format ‘plus’ (EDF+), an EDF alike standard format for the exchange of physiological data. Clin Neurophysiol 114:1755–1761CrossRefGoogle Scholar
  37. Kemp B, Värri A, Rosa AC, Nielsen KD, Gade J (1992) A simple format for exchange of digitized polygraphic recordings. Electroencephalogr Clin Neurophysiol 82:391–393CrossRefGoogle Scholar
  38. Kwak S, Weiss JH (2006) Calcium-permeable AMPA channels in neurodegenerative disease and ischemia. Curr Opin Neurobiol 16:281–287CrossRefGoogle Scholar
  39. Lallement G, Clarençon D, Masqueliez C, Baubichon D, Galonnier M, Burckhart MF, Peoc’h M, Mestries JC (1998a) Nerve agent poisoning in primates: antilethal, anti-epileptic and neuroprotective effects of GK-11. Arch Toxicol 72:84–92CrossRefGoogle Scholar
  40. Lallement G, Dorandeu F, Filliat P, Carpentier P, Baille V, Blanchet G (1998b) Medical management of organophosphate-induced seizures. J Physiol Paris 92:369–373CrossRefGoogle Scholar
  41. Langston JL, Wright LK, Connis N, Lumley LA (2012) Characterizing the behavioral effects of nerve agent-induced seizure activity in rats: increased startle reactivity and perseverative behavior. Pharmacol Biochem Behav 100:382–391Google Scholar
  42. Leung YM, Tzeng JI, Gong CL, Wang YW, Chen YW, Wang JJ (2015) Caramiphen-induced block of sodium currents and spinal anesthesia. Eur J Pharmacol 746:213–220Google Scholar
  43. Li JM, Zeng YJ, Peng F, Li L, Yang TH, Hong Z, Lei D, Chen Z, Zhou D (2010) Aberrant glutamate receptor 5 expression in temporal lobe epilepsy lesions. Brain Res 1311:166–174CrossRefGoogle Scholar
  44. Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT (2007) NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci 27:2846–2857CrossRefGoogle Scholar
  45. McDonough JH Jr, Shih TM (1997) Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci Biobehav Rev 21:559–579CrossRefGoogle Scholar
  46. McDonough JH Jr, McLeod CG Jr, Nipwoda MT (1987) Direct microinjection of soman or VX into the amygdala produces repetitive limbic convulsions and neuropathology. Brain Res 435:123–137CrossRefGoogle Scholar
  47. McDonough JH Jr, Clark TR, Slone TW Jr, Zoeffel D, Brown K, Kim S, Smith CD (1998) Neural lesions in the rat and their relationship to EEG delta activity following seizures induced by the nerve agent soman. Neurotoxicology 19:381–391PubMedGoogle Scholar
  48. Mercey G, Verdelet T, Renou J, Kliachyna M, Baati R, Nachon F, Jean L, Renard PY (2012) Reactivators of acetylcholinesterase inhibited by organophosphorus nerve agents. Acc Chem Res 45:756–766CrossRefGoogle Scholar
  49. Miller SL, Aroniadou-Anderjaska V, Pidoplichko VI, Figueiredo TH, Apland JP, Krishnan JK, Braga MF (2017) The M1 muscarinic receptor antagonist VU0255035 delays the development of status epilepticus after organophosphate exposure and prevents hyperexcitability in the basolateral amygdala. J Pharmacol Exp Ther 360:23–32CrossRefGoogle Scholar
  50. Naylor DE, Liu H, Wasterlain CG (2005) Trafficking of GABA(a) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci 25:7724–7733CrossRefGoogle Scholar
  51. Naylor DE, Liu H, Niquet J, Wasterlain CG (2013) Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus. Neurobiol Dis 54:225–238CrossRefGoogle Scholar
  52. Niquet J, Baldwin R, Suchomelova L, Lumley L, Naylor D, Eavey R, Wasterlain CG (2016) Benzodiazepine-refractory status epilepticus: pathophysiology and principles of treatment. Ann N Y Acad Sci 1378:166–173Google Scholar
  53. Niquet J, Baldwin R, Suchomelova L, Lumley L, Eavey R, Wasterlain CG (2017) Treatment of experimental status epilepticus with synergistic drug combinations. Epilepsia 58:e49–e53CrossRefGoogle Scholar
  54. Pan H, Piermartiri TC, Chen J, McDonough J, Oppel C, Driwech W, Winter K, McFarland E, Black K, Figueiredo T, Grunberg N, Marini AM (2015) Repeated systemic administration of the nutraceutical alpha-linolenic acid exerts neuroprotective efficacy, an antidepressant effect and improves cognitive performance when given after soman exposure. Neurotoxicology 51:38–50CrossRefGoogle Scholar
  55. Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 4th edn. Elsevier, New YorkGoogle Scholar
  56. Pontecorvo MJ, Karbon EW, Goode S, Clissold DB, Borosky SA, Patch RJ, Ferkany JW (1991) Possible cerebroprotective and in vivo NMDA antagonist activities of sigma agents. Brain Res Bull 26:461–465CrossRefGoogle Scholar
  57. Portera-Cailliau C, Price DL, Martin LJ (1997) Non-NMDA and NMDA receptor-mediated excitotoxic neuronal deaths in adult brain are morphologically distinct: further evidence for an apoptosis-necrosis continuum. J Comp Neurol 378:88–104CrossRefGoogle Scholar
  58. Prager EM, Aroniadou-Anderjaska V, Almeida-Suhett CP, Figueiredo TH, Apland JP, Braga MF (2013) Acetylcholinesterase inhibition in the basolateral amygdala plays a key role in the induction of status epilepticus after soman exposure. Neurotoxicology 38:84–90CrossRefGoogle Scholar
  59. Prager EM, Aroniadou-Anderjaska V, Almeida-Suhett CP, Figueiredo TH, Apland JP, Rossetti F, Olsen CH, Braga MF (2014a) The recovery of acetylcholinesterase activity and the progression of neuropathological and pathophysiological alterations in the rat basolateral amygdala after soman-induced status epilepticus: relation to anxiety-like behavior. Neuropharmacology 81:64–74CrossRefGoogle Scholar
  60. Prager EM, Pidoplichko VI, Aroniadou-Anderjaska V, Apland JP, Braga MF (2014b) Pathophysiological mechanisms underlying increased anxiety after soman exposure: reduced GABAergic inhibition in the basolateral amygdala. Neurotoxicology 44:335–343CrossRefGoogle Scholar
  61. Prager EM, Figueiredo TH, Long RP 2nd, Aroniadou-Anderjaska V, Apland JP, Braga MF (2015) LY293558 prevents soman-induced pathophysiological alterations in the basolateral amygdala and the development of anxiety. Neuropharmacology 89:11–18CrossRefGoogle Scholar
  62. Qashu F, Figueiredo TH, Aroniadou-Anderjaska V, Apland JP, Braga MF (2010) Diazepam administration after prolonged status epilepticus reduces neurodegeneration in the amygdala but not in the hippocampus during epileptogenesis. Amino Acids 38:189–197CrossRefGoogle Scholar
  63. Rajasekaran K, Joshi S, Kozhemyakin M, Todorovic MS, Kowalski S, Balint C, Kapur J (2013) Receptor trafficking hypothesis revisited: plasticity of AMPA receptors during established status epilepticus. Epilepsia 54:14–16CrossRefGoogle Scholar
  64. Ramsay RE, Hammond EJ, Perchalski RJ, Wilder BJ (1979) Brain uptake of phenytoin, phenobarbital, and diazepam. Arch Neurol 36:535–539Google Scholar
  65. Raveh L, Chapman S, Cohen G, Alkalay D, Gilat E, Rabinovitz I, Weissman BA (1999) The involvement of the NMDA receptor complex in the protective effect of anticholinergic drugs against soman poisoning. Neurotoxicology 20:551–559PubMedGoogle Scholar
  66. Raveh L, Brandeis R, Gilat E, Cohen G, Alkalay D, Rabinovitz I, Sonego H, Weissman BA (2003) Anticholinergic and antiglutamatergic agents protect against soman-induced brain damage and cognitive dysfunction. Toxicol Sci 75:108–116CrossRefGoogle Scholar
  67. Raveh L, Rabinovitz I, Gilat E, Egoz I, Kapon J, Stavitsky Z, Weissman BA, Brandeis R (2008) Efficacy of antidotal treatment against sarin poisoning: the superiority of benactyzine and caramiphen. Toxicol Appl Pharmacol 227:155–162CrossRefGoogle Scholar
  68. Rogawski MA, Gryder D, Castaneda D, Yonekawa W, Banks MK, Lia H (2003) GluR5 kainate receptors, seizures, and the amygdala. Ann N Y Acad Sci 985:150–162CrossRefGoogle Scholar
  69. Schultz MK, Wright LK, Stone MF, Schwartz JE, Kelley NR, Moffett MC, Lee RB, Lumley LA (2012) The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: synergism with the benzodiazepine diazepam. Toxicol Appl Pharmacol 259:376–386CrossRefGoogle Scholar
  70. Schultz MK, Wright LK, de Araujo FM, Stone MF, Moffett MC, Kelley NR, Bourne AR, Lumeh WZ, Schultz CR, Schwartz JE, Lumley LA (2014) Caramiphen edisylate as adjunct to standard therapy attenuates soman-induced seizures and cognitive deficits in rats. Neurotoxicol Teratol 44:89–104CrossRefGoogle Scholar
  71. Shih TM, McDonough JH Jr (1999) Organophosphorus nerve agents-induced seizures and efficacy of atropine sulfate as anticonvulsant treatment. Pharmacol Biochem Behav 64:147–153CrossRefGoogle Scholar
  72. Shih TM, Penetar DM, McDonough JH Jr, Romano JA, King JM (1990) Age-related differences in soman toxicity and in blood and brain regional cholinesterase activity. Brain Res Bull 24:429–436CrossRefGoogle Scholar
  73. Shih TM, Duniho SM, McDonough JH Jr (2003) Control of nerve agent-induced seizures is critical for neuroprotection and survival. Toxicol Appl Pharmacol 188:69–80Google Scholar
  74. Sirin GS, Zhou Y, Lior-Hoffmann L, Wang S, Zhang Y (2012) Aging mechanism of soman inhibited acetylcholinesterase. J Phys Chem B 116:12199–12207CrossRefGoogle Scholar
  75. Skovira JW, McDonough JH Jr, Shih TM (2010) Protection against sarin-induced seizures in rats by direct brain microinjection of scopolamine, midazolam or MK-801. J Mol Neurosci 40:56–62CrossRefGoogle Scholar
  76. Sohal VS, Zhang F, Yizhar O, Deisseroth K (2009) Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459:698–702CrossRefGoogle Scholar
  77. Solberg Y, Belkin M (1997) The role of excitotoxicity in organophosphorous nerve agents central poisoning. TiPS 18:183–185PubMedGoogle Scholar
  78. Stark E, Eichler R, Roux L, Fujisawa S, Rotstein HG, Buzsáki G (2013) Inhibition-induced theta resonance in cortical circuits. Neuron 80:1263–1276CrossRefGoogle Scholar
  79. Thurgur C, Church J (1998) The anticonvulsant actions of sigma receptor ligands in the Mg2+-free model of epileptiform activity in rat hippocampal slices. Br J Pharmacol 124:917–929CrossRefGoogle Scholar
  80. Trinka E, Kälviäinen R (2017) 25 years of advances in the definition, classification and treatment of status epilepticus. Seizure 44:65–73CrossRefGoogle Scholar
  81. Ullal G, Fahnestock M, Racine R (2005) Time-dependent effect of kainate-induced seizures on glutamate receptor GluR5, GluR6, and GluR7 mRNA and protein expression in rat hippocampus. Epilepsia 46:616–623CrossRefGoogle Scholar
  82. Vismer MS, Forcelli PA, Skopin MD, Gale K, Koubeissi MZ (2015) The piriform, perirhinal, and entorhinal cortex in seizure generation. Front Neural Circuits 29:9–27Google Scholar

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Authors and Affiliations

  • James P. Apland
    • 1
  • Vassiliki Aroniadou-Anderjaska
    • 2
    • 3
  • Taiza H. Figueiredo
    • 2
  • Marcio De Araujo Furtado
    • 2
  • Maria F. M. Braga
    • 2
    • 3
  1. 1.Neuroscience ProgramU.S. Army Medical Research Institute of Chemical DefenseAberdeenUSA
  2. 2.Department of Anatomy, Physiology, and Genetics, F. Edward Hébert School of MedicineUniformed Services University of the Health SciencesBethesdaUSA
  3. 3.Department of Psychiatry, F. Edward Hébert School of MedicineUniformed Services University of the Health SciencesBethesdaUSA

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