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系統識別號 U0026-0812200911151942
論文名稱(中文) 單純疱疹病毒誘發實驗性抽搐之致病機制探討
論文名稱(英文) Pathogenesis of Herpes Simplex Virus Induced Experimental Seizures in Mice
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 92
學期 2
出版年 93
研究生(中文) 吳鴻明
研究生(英文) Hung-Ming Wu
電子信箱 epitsai@mail.ncku.edu.tw
學號 s5887104
學位類別 博士
語文別 英文
論文頁數 142頁
口試委員 口試委員-陳舜華
指導教授-許桂森
口試委員-陳順勝
召集委員-簡伯武
口試委員-吳豐森
口試委員-陳慶鏗
口試委員-華瑜
指導教授-蔡景仁
中文關鍵字 癲癇,病毒性腦炎,單純疱疹病毒第1型,單純疱疹病毒腦炎,小鼠動物模型,海馬迴薄片,致抽搐化學藥(pentylenetetrazol,kainic acid),錄影行為觀察,深部電極腦波記錄,SK2基因,抗病毒藥物 
英文關鍵字 herpes simplex virus type 1 (HSV-1)  epilepsy  viral encephalitis  mouse model  herpes simplex virus encephalitis (HSVE)  hippocampal slices  pentylenetetrazol  kainic acid  video behavioral monitoring  depth electrode electroencephalography  valacyclovir  SK2 gene 
學科別分類
中文摘要   癲癇症續發於病毒性腦炎已相當地明確,單純疱疹病毒第1型是一種中樞神經感染後造成人類癲癇症最有關的病原體。然而,病毒造成癲癇症的致病病理和機制至今仍不明。在此,我們建立單純疱疹病毒腦炎的小鼠動物模型,其臨床症狀與病理變化和人類的疱疹腦炎極為相似,適用於研究單純疱疹病毒和其致癲癇的相關性探討。經由角膜感染病毒,小鼠主要病理變化位於額顳區和腦幹區,與疱疹病毒抗原的表現位置一致。感染疱疹病毒產生腦膜腦炎,臨床上可觀察到各種不同程度的抽搐行為,以深部電極記錄可以在海馬迴區域記錄到類癲癇波的發生。在電生理方面,在海馬迴薄片CA3區上存活的椎狀神經元的靜止膜電位有明顯的去極化現象並伴隨著細胞膜阻抗的增加,動作電位後再極化的振幅也明顯地減少,而且易於產生同步性的神經衝動,對突觸 (synapse)性的傳遞則易於誘發神經衝動與發射(firing),這些現象的表現可從急性期一直延續到慢性期。在活體實驗方面,這些急性期存活的小鼠及至慢性期的小鼠對於致癲癇抽搐藥品(如pentylenetetrazol及kainic acid)的抽搐閥值皆明顯的降低。進一步,透過深部電極記錄和行為觀察,可以在存活小鼠感染後約百天後發現自發性的抽搐行為發作行為亦即”癲癇”的發生,其發生率在感染後120天約為20%,而在210天約為41%。此外,在急性期存活小鼠病理病灶變化,我們發現其病理病灶多分佈於梨形區,杏仁區和腦幹區,較少數在海馬迴處。經組織免疫染色發現此區有許多的神經退化性神經細胞。利用PCR測量疱疹病毒的DNA ,也印證了病毒DNA大多潛藏於此顳葉區,這個結果與致癲癇發生區相符。另外,我們亦發現在海馬迴CA3區域有神經突觸漸進地萌芽重新組織的現象,及長期持續星狀體細胞增生和活化的現象。由於SK2基因所對應的蛋白為鈣離子所活化之鉀離子管道,其主要功能為參與動作電位後再極化的發生,經由北方點墨法和西方點墨法測定,發現受感染的小鼠海馬迴CA3區的SK2mRNA及蛋白的表現有明顯的下降。在藥物治療方面,感染的小鼠即早施於抗病毒藥物治療,發現可減少腦組織受損的程度,並提昇小鼠對化學性致癲癇藥品的抽搐閥值。綜合以上的結果,顯示單純疱疹病毒第1型感染確能造成降低抽搐閥值及癲癇,而長期神經細胞去極化,動作電位後再極化功能不全,神經細胞間的胞突萌芽重組,將是致癲癇的細胞病態生理機制;持續地單純疱疹病毒和活化的星狀體細胞存於病變處,將改變神經間的環境而加重細胞的興奮狀態,終至續發成癲癇,此結果將可提供未來治療疱疹性癲癇症的重要參考。
英文摘要   Epilepsy is well recognized as a sequel of viral encephalitis. Herpes simplex virus type 1 (HSV-1) is the most notorious pathogen in patients with acquired epilepsy after CNS viral infection. However, little is known about the pathogenesis of epilepsy after HSV-1 infection. Here, we developed a suitable mouse model of HSV encephalitis (HSVE) mimicking characteristics of HSVE in human to address the relationship of epilepsy and HSV-1 infections. The pathological lesions of mice inoculated with HSV-1 on the right corneal were widely distributed in frontotemporal regions, including piriform cortex, amygdale, hippocampus, brain stem, and other cortical regions correlated with the localization of viral antigens. Clinical observation found high incidence of reactive motor seizure behaviors correlated with ictal discharges usually originated from hippocampal regions at acute stage of HSVE in mice, which was confirmed by depth electrode recordings. In in vitro electrophysiological study, the surviving CA3 pyramidal cells in the hippocampal slices exhibited a more depolarizing resting membrane potential concomitant with an increase in membrane input resistance, and had a lower threshold to generate synchronized bursts as well as a significant decrease in the amplitude of afterhyperpolarization (AHP) than controls, which were persistent from acute infection till latent infection period. In addition, as the paired stimuli applied, synaptic transmission was easily evoked to epileptiform discharges in CA3 regions of the slices of infected mice. In in vivo study, it was found that the mice surviving from HSVE had increased short- and long-term seizure susceptibility to limbic convulsants (pentylenetetrazol and kainic acid) later in life compared with age-matched controls. Expectably, the surviving mice did display subclinical and recurrent seizure behaviors post inoculation. Extensive hippocampal electroencephalographic and behavioral monitoring demonstrated spontaneous seizures developed in 21 % and 41 % of infected mice by 120 and 210 days after inoculation, respectively; EEG seizures in another 21% and 17%, respectively. Immunocytochemical analyses revealed that most common initial brain lesions among surviving mice were located in piriform cortex, amygdale, and brain stem, and a few in CA3 subfield of hippocampus, but rare active neurodegeneration in these regions was noted during latently infected period. HSV-1 genomes were dominantly found in temporal regions and correlated to a high degree of subsequent seizure severity. Progressive mossy fiber sprouting in hippocampus and persistent astrocyte reactivation occurred in limbic structures of infected mice. As shown by Northern and Western blotting analyses, the expression of the transcripts and protein of the small-conductance Ca2+-activated potassium channel type 2 (SK2) gene were significantly less prominent in CA3 subfield during HSV-1 infection when compared with controls. Treatment of HSV-1-infected mice with valacyclovir, a potent inhibitor of HSV-1 replication, produced a dose-dependent reduction on the signs of neurological deficits, pathological damages, and pentylenetetrazol-induced seizure severity. These results showed that HSV-1 infection in mice can lower seizure threshold to chemical convulsants and cause spontaneous limbic seizures later in life. The long-lasting neuronal depolarization, AHP dysfunction, and progressive synaptic reorganization in limbic regions may contribute to the basic processes of epileptogenesis of HSV-1 infection. Persistently latent viral genomes and reactive astrocytes in initial precipitating sites of HSVE may influence the microenvironment of brain tissues and enhance excitability of these neural tissues and loops. Taken together, they would facilitate the subsequent development of epilepsy. These findings may provide new therapeutic potentials for epilepsy associated with HSV-1infection.
論文目次 Abstract in Chinese 1
Abstract in English 4
Abbreviations 7
INTRODUCTION 11
1-1. Structures and genes of herpes simplex virus type 1 12
1-2. The pathway of HSV-1 infection 12
1-3. HSV-1 encephalitis 13
1-4. HSV-1 entry 13
1-5. HSV-1 latency 14
1-6. Definitions of seizure and epilepsy 15
1-7. Epilepsy in humans 15
1-8. HSV-1 and epilepsy 16
1-9. Motive and goal of the research 17

MATERIALS AND METHODS 27
2-1. Herpes simplex viruses and cells 28
2-2. Infection of animal and tissue collection 28
2-3. Clinical evaluation and definition of HSVE 28
2-4. Antiviral drug treatment and measurement of clinical signs 29
2-5. In vivo depth electroencephalographic recordings 29
2-6. Hippocampal slice preparations and electrophysiological studies 30
2-7. Histopathological and immunocytochemistric studies 31
2-8. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling
(TUNEL) 33
2-9. Timm staining and scoring 34
2-10. Detection of HSV-1 DNA by quantitative PCR 35
2-11. Northern and Western blots 36
2-12. Cell counts 37
2-13. Determination of susceptibility to pentylenetetrazol-induced limbic
seizures 38
2-14. Determination of threshold to kainic acid-induced limbic seizures
(1) 39
2-15. Determination of seizure threshold induced by kainic acid in infected mice
(2) 40
2-16. Analysis for spontaneous and EEG seizures in HSV-1 infected mice
41
2-17. Statistical analysis 42

RESULTS AND DISCUSSION 43
3-1. HSV-1 inoculation enhances hippocampal excitability in mice 43
3-2. HSV-1 infected mice persistently increased susceptibility to
chemoconvulsant-induced seizure, which can be ameliorated by antiviral drug 71
3-3. HSV-1 infection causes a long-lasting increase in neuronal excitability and
spontaneous seizure evolution in mice 95

CONCLUSION 118
REFERENCES 122
LISTS of TABLES and FIGURES 140
參考文獻 1. Annegers, J.F., Hauser, W.A., Beghi, E., Nicolosi, A. & Kurland, L.T. (1988) The risk of unprovoked seizures after encephalitis and meningitis. Neurology 38, 1407-1410.
2. Babb, T.L., Kupfer, W.R., Pretorius, J.K., Crandall, P.H. & Levesque, M.F. (1991) Synaptic reorganization by mossy fibers in human epileptic fascia dentata. Neuroscience 42, 351-363.
3. Baichwal, V.R. & Sugden, B. (1988) Latency comes of age for herpesviruses. Cell 52, 787-789.
4. Baker, D.A. (2002) Valacyclovir in the treatment of genital herpes and herpes zoster. Expert. Opin. Pharmacother. 3, 51-58.
5. Barnes. D.W. & Whitley. RJ. (1986) CNS diseases associated with varicella zoster virus and herpes simplex virus infection. Pathogenesis and current therapy. Neurol Clin. 4, 265-283.
6. Baringer, J.R. & Pisani, P. (1994) Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction. Ann. Neurol. 36, 823-829.
7. Beers, D.R., Henkel, J.S., Schaefer, D.C., Rose, J.W. & Stroop, W.G. (1993) Neuropathology of herpes simplex virus encephalitis in a rat seizure model. J. Neuropathol. Exp. Neurol. 52, 241-252.
8. Ben-Ari, Y., Lagowska, J., Tremblay, E. & Le Gal La Salle, G..A. (1979) new model of focal status epilepticus: intra-amygdaloid application of kainic acid elicits repetitive secondarily generalized convulsive seizures. Brain Res. 163, 176-179.
9. Ben-Ari, Y., Tremblay, E., Riche, D., Ghilini, G. & Naquet, R. (1981) Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentetrazole: metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy. Neuroscience. 6, 1361-1391.
10. Ben-Ari, Y. (1985) Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14, 375-403.
11. Ben-Ari, Y. & Cossart, R. (2000) Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci. 23, 580-587.
12. Bengzon, J., Kokaia, Z., Elmer, E., Nanobashvili, A., Kokaia, M. & Lindvall, O. (1997) Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci U S A. 94, 10432-10437.
13. Bernard, C. & Wheal, H.V. (1995) Plasticity of AMPA and NMDA receptor-mediated epileptiform activity in a chronic model of temporal lobe epilepsy. Epilepsy Res. 21, 95-107.
14. Blatz, A.L. & Magleby. K.L (1986) Single apamin-blocked Ca-activated K+ channels of small conductance in cultured rat skeletal muscle. Nature. 323, 718-720.
15. Boerman, R.H., Peters, A.C., Bloem, B.R., Raap, A.K. & van der Ploeg, M. (1992) Spread of herpes simplex virus to the cerebrospinal fluid and the meninges in experimental mouse encephalitis. Acta Neuropathol. 83, 300-307.
16. Bragin, A., Wilson, C.L. & Engel, J. Jr. (2000) Chronic epileptogenesis requires development of a network of pathologically interconnected neuron clusters: a hypothesis. Epilepsia 41, S144-S152.
17. Brody, T.M., Larner, J. & Minneman, K.P. (1998) Human pharmacology: molecular to clinical, Mosby-Year Book, Inc..
18. Browning, R.A. (1987) Effect of lesions on seizures in experimental nimals, in Epilepsy and the reticular Formation: the Role of the Reticular Core in Convulsive seizures, Fromm, G. H., Faingold, C. L., Browning, R. A., and Burnham, W. M., Eds., Alan R. Liss, New York, 137-162.
19. Browning, R.A., Wang, C. & Faingold, C.L. (1991) Effect of norepinephrine depletion on audiogenic-like seizures elicited by microinfusion of an excitant amino acid into the inferior colliculus of normal rats. Exp. Neurol. 112, 200-205.
20. Brunson, K.L., Eghbal-Ahmadi, M., Bender, R., Chen, Y. & Baram, T.Z. (2001) Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress. Proc. Natl. Acad. Sci. U. S. A. 98, 8856-8861.
21. Bush, P.C., Prince, D.A. & Miller, K.D. (1999) Increased pyramidal excitability and NMDA conductance can explain posttraumatic epileptogenesis without disinhibition: a model. J Neurophysiol. 82, 1748-1758.
22. Cavazos, J.E, Golarai, G.. & Sutula, T.P. (1991) Mossy fiber synaptic reorganization induced by kindling: time course of development, progression, and permanence. J. Neurosci. 11, 2795-2803.
23. Cesario, T.C., Poland, J.D., Wulff, H., Chin, T.D. & Wenner, H.A. (1969) Six years experience with herpes simplex virus in a children's home. Am J Epidemiol. 90, 416-422.
24. Chen, S. F., Huang, C. C., Wu, H. M., Chen, S. H., Liang, Y. C. & Hsu, K. S. (2004) Seizure, neuronal loss, and mossy fiber sprouting in herpes simplex virus type-1-infected organotypic hippocampal cultures. Epilepsia. 41, 1-11.
25. Chen, S.H., Kramer, M.F., Schaffer, P.A. & Coen, D.M. (1997) A viral function represses accumulation of transcripts from productive-cycle genes in mouse ganglia latently infected with herpes simplex virus. J. Virol. 71, 5878-5884.
26. Chen, S.H., Garber, D.A., Schaffer, P.A., Knipe, D.M. & Coen, D.M. (2000) Persistent elevated expression of cytokine transcripts in ganglia latently infected with herpes simplex virus in the absence of ganglionic replication or reactivation. Virology 278, 207-216.
27. Cho, C.T., Feng & K.K. (1980) Combined effects of acycloguanosine and humoral antibodies in experimental encephalitis due to Herpesvirus hominis. J. Infect. Dis. 142, 451.
28. Coen, D.M., Fleming, H.E., Jr Leslie, L.K. & Retondo, M.J. (1985) Sensitivity of arabinosyladenine-resistant mutants of herpes simplex virus to other antiviral drugs and mapping of drug hypersensitivity mutations to the DNA polymerase locus. J. Virol. 53, 477-488.
29. Coen, D.M., Kosz-Vnenchak, M., Jacobson, J.G., Leib, D.A., Bogard, C.L., Schaffer, P.A., Tyler, K.L. & Knipe, D.M. (1989) Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate. Proc. Natl. Acad. Sci. USA. 86, 4736-4740.
30. Cole, A.E. & Nicoll, R.A. (1983) Acetylcholine mediates a slow synaptic potential in hippocampal pyramidal cells. Science 221, 1299-1301.
31. Colino, A. & Halliwell, J.V. (1987) Differential modulation of three separate K-conductances in hippocampal CA1 neurons by serotonin. Nature 328, 73-77.
32. Cornell-Bell, A.H. & Williamson, A. (1993) Hyperexcitabilty of neurons and astrocytes in epileptic human cortex. In: Fedoroff, s., Juurlink, B.H.J. & Doucette, R. Biology and pathology of astrocyte-neuron interaction, Plenum Press, New York, 51-65.
33. Cornford, M.E. & McCormick, G.F. (1997) Adult-onset temporal lobe epilepsy associated with smoldering herpes simplex 2 infection. Neurology 48, 425-430.
34. Cornish, S.M. & Wheal, H.V. (1989) Long-term loss of paired pulse inhibition in the kainic acid-lesioned hippocampus of the rat. Neuroscience 28, 563-571.
35. Cronin, J. & Dudek, F.E. (1988) Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res. 474, 181-184.
36. Cutrufo, C., Bortot, L., Giachetti, A. & Manzini, S. (1992) Differential effects of various xanthines on pentylenetetrazole-induced seizures in rats: an EEG and behavioural study. Eur. J. Pharmacol. 222, 1-6.
37. Davies, C.H., Davies, S.N. & Collingridge, G.L. (1990) Paired-pulse depression of monosynaptic GABA-mediated inhibitory postsynaptic responses in rat hippocampus. J. Physiol. 424, 513-531.
38. Davis, L.E. & Johnson, R.T. (1979) An explanation for the localization of herpes simplex encephalitis? Ann. Neurol. 5, 2-5.
39. De Graff, A.S. (1974) Epidemiological aspects of epilepsy in Northern Norway. Epilepsia 15, 291-299.
40. Dean, P. & ale, K. (1989) Anticonvulsant action of GABA receptor blockade in the nigrotectal target region. Brain Res. 477, 391-395.
41. Deatly, A.M., Spivack, J.G., Lavi, E. & Fraser, N.W. (1987) RNA from an immediate early region of the type 1 herpes simplex virus genome is present in the trigeminal ganglia of latently infected mice. Proc.Natl.Acad.Sci.U S A. 84, 3204-3208.
42. Devi-Rao, G.B., Bloom, D.C., Stevens, J.G. & Wagner, E.K. (1994) Herpes simplex virus type 1 DNA replication and gene expression during explant-induced reactivation of latently infected murine sensory ganglia. J Virol. 68, 1271-1282.
43. Druga, R., Kubova, H., Suchomelova, L. & Haugvicova, R. (2003) Lithium/pilocarpine status epilepticus-induced neuropathology of piriform cortex and adjoining structures in rats is age-dependent. Physiol Res. 52, 251-264.
44. Dube, C., Chen, K., Eghbal-Ahmadi, M., Brunson, K., Soltesz, I. & Baram, T.Z. (2000) Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term. Ann. Neurol. 47, 336-344.
45. El Hamdi, G., de Vasconcelos, A.P., Vert, P. & Nehlig, A. (1992) An experimental model of generalized seizures for the measurement of local cerebral glucose utilization in the immature rat. I. Behavioral characterization and determination of lumped constant. Dev. Brain Res. 69, 233-242.
46. Esiri, M.M. (1982) Herpes simplex encephalitis: immunohistological study of the distribution of viral antigen within the brain. J. Neurol. Sci. 54, 209-226.
47. Feldblum, S. & Ackermann, R.F. (1987) Increased susceptibility to hippocampal and amygdala kindling following intrahippocampal kainic acid. Exp. Neurol. 97, 255-269.
48. Ferraro, T.N., Golden, G.T., Smith, G.G., St Jean, P., Schork, N.J., Mulholland, N., Ballas, C., Schill, J., Buono, R.J. & Berrettini, W.H. (1999) Mapping loci for pentylenetetrazol-induced seizure susceptibility in mice. J. Neurosci. 19, 6733-6739.
49. Floyd, R. A. & Hensley, K. (2003) Neuroinflammation-mediated neurotoxin production in neurodegenerative diseases, in Neuroinflammation: Mechanisms and Management, Wood, P. L. Eds., Human Press, New Jersey, 171-186.
50. Fodor, P.A., Levin, M.J., Weinberg, A., Sandberg, E., Sylman, J. & Tyler, K.L. (1998) Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF. Neurology 51, 554-559.
51. Fraser, N.W. & Valyi-Nagy, T. (1993) Viral, neuronal and immune factors which may influence herpes simplex virus (HSV) latency and reactivation. Microb Pathog. 15, 83-91.
52. Gannicliffe, A., Saldanha, J.A., Itzhaki, R.F. & Sutton, R.N. (1985) Herpes simplex viral DNA in temporal lobe epilepsy. Lancet 1, 214-215.
53. Golarai, G., Cavazos, J.E. & Sutula, T.P. (1992) Activation of the dentate gyrus by pentylenetetrazol evoked seizures induces mossy fiber synaptic reorganization. Brain Res. 593, 257-264.
54. Grossman, S.P. (1963) Chemically induced epileptiform seizures in the cat. Science 142, 409-11.
55. Haas, H.L. & Konnerth, A. (1983) Histamine and noradrenaline decrease calcium-activated potassium conductance in hippocampal pyramidal cells. Nature 302, 432-434.
56. Hablitz, J.J. & Johnston, D. (1981) Endogenous nature of spontaneous bursting in hippocampal pyramidal neurons. Cell Mol. Neurobiol. 1, 325-334.
57. Habu, S., Akamatsu, K., Tamaoki, N. & Okumura, K. (1984) In vivo significance of NK cell on resistance against virus (HSV-1) infections in mice. J. Immunol. 133, 2743-2747.
58. Haglund, M.M., Stahl, W.L., Kunkel, D.D. & Schwartzkroin, P.A. (1985) Developmental and regional differences in the localization of Na,K-ATPase activity in the rabbit hippocampus. Brain Res. 343, 98-203.
59. Haglund, M.M. & Schwartzkroin, P.A. (1990) Role of Na-K pump potassium regulation and IPSPs in seizures and spreading depression in immature rabbit hippocampal slices. J. Neurophysiol. 63, 25-239.
60. Hauser, W.A. & Kurland, L.T. (1975) The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 16, 1-66.
61. Hill, J.M., Dudley, J.B, Shimomura, Y. & Kaufman, H.E. (1986) Quantitation and kinetics of induced HSV-1 ocular shedding. Curr Eye Res. 5, 241-246.
62. Horsburgh, B. C., Chen, S.H., Hu, A., Mulamba, G.B., Burns, W.H. & Coen, D.M. (1998) Recurrent acyclovir-resistant herpes simplex virus in an immunocompromised patient: can strain differences compensate for loss of thymidine kinase in pathogenesis? J. Infect. Dis. 178:618-625.
63. Hsieh, C.L., Tang, N.Y., Chiang, S.Y., Hsieh, C.T. & Lin, J.G. (1999) Anticonvulsive and free radical scavenging actions of two herbs, Uncaria rhynchophylla (MIQ) Jack and Gastrodia elata Bl., in kainic acid-treated rats. Life Sci. 65, 2071-2082.
64. Huang, C.C. & Hsu, K.S. (1999) Protein tyrosine kinase is required for the induction of long-term potentiation in the rat hippocampus. J. Physiol. 520, 783-796.
65. Ito, T., Hori, M., Yoshida, K. & Shimizu, M. (1977) Effect of anticonvulsants on seizures developing in the course of daily administration of pentetrazol to rats. Eur. J. Pharmacol. 45, 165-172.
66. Jensen, M.S., Azouz, R. & Yaari, Y. (1994) Variant firing patterns in rat hippocampal pyramidal cells modulated by extracellular potassium. J. Neurophysiol. 71, 831-839.
67. Johnson, R.T. (1964) The pathogenesis of herpes virus encephalitis. II. A cellular basis for the development of resistance with age. J. Exp. Med. 120, 359-374.
68. Katz, J. P., E. T. Bodin, & D. M. Coen. (1990) Quantitative polymerase chain reaction analysis of herpes simplex virus DNA in ganglia of mice infected with replication-incompetent mutants. J. Virol. 64:4288-4295.
69. Kern, E.R., Richards, J.T., Glasgow, L.A., Overall, J.C. Jr. & de Miranda, P. (1982) Optimal treatment of herpes simplex virus encephalitis in mice with oral acyclovir. Am. J. Med. 73, 125-131.
70. Khurgel, M. & Ivy GO. (1996) Astrocytes in kindling: relevance to epileptogenesis.Epilepsy Res. 26, 163-175.
71. Klapper, P.E., Cleator, G.M. & Longson, M. (1984) Mild forms of herpes encephalitis. J. Neuro. Neurosurg. Psychiatry 47, 1247-1250.
72. Knaus, H.G., Eberhart, A., Koch, R.O., Munujos, P., Schmalhofer, W.A., Warmke, J.W., Kaczorowski, G.J. & Garcia, M.L. (1995) Characterization of tissue-expressed alpha subunits of the high conductance Ca(2+)-activated K+ channel. J Biol Chem. 270, 22434-22439.
73. Knotts, F.B. & Cook, M.L. (1974) Stevens JG.Pathogenesis of herpetic encephalitis in mice after ophthalmic inoculation. J Infect Dis.130,16-27.
74. Kramer, M.F., & Coen, D.M. (1995) Quantification of transcripts from the ICP4 and thymidine kinase genes in mouse ganglia latently infected with herpes simplex virus. J Virol. 69, 1389-1399.
75. Kristensson, K., Nennesmo, L., Persson, L. & Lycke, E. (1982) Neuron to neuron transmission of herpes simplex virus. Transport of virus from skin to brainstem nuclei. J. Neurol. Sci. 54, 149-156.
76. Lausch, R.N., Kleinschradt, W.R., Monteiro, C., Kayes, S.G. & Oakes, J.E. (1985) Resolution of HSV corneal infection in the absence of delayed-type hypersensitivity. Invest. Ophthalmol. Vis. Sci. 26, 1509-1515.
77. Lai, C.W.& Gragasin, M.E. (1988) Electroencephalography in herpes simplex encephalitis. J. Clin. Neurophysil. 5, 87-103.
78. LeBlanc, R.A., Pesnicak, L., Godleski, M. & Straus, S.E. (1999) The comparative effects of famciclovir and valacyclovir on herpes simplex virus type 1 infection, latency, and reactivation in mice. J. Infect. Dis. 180, 594-599.
79. Leib, D.A., Coen, D.M., Bogard, C.L., Hicks, K.A., Yager, D.R., Knipe, D.M., Tyler, K.L. & Schaffer, P.A. (1989) Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency. J. Virol. 63, 759-768.
80. Lewandowski, G. & Hobbs, M.V. (1998) Evidence for deficiencies in intracerebral cytokine production, adhesion molecule induction, and T cell recruitment in herpes simplex virus type-2 infected mice. J. Neuroimmunol. 81, 58-65.
81. Lewandowski, G., Hobbs, M.V. & Bloom, F.E. (1994) Alteration of intracerebral cytokine production in mice infected with herpes simplex virus types 1 and 2. J. Neuroimmunol. 55, 23-34.
82. Lewandowski, G., Hobbs, M. & Geller, A. (1998) Evidence that deficient IFN-gamma production is a biological basis of herpes simplex virus type-2 neurovirulence. J. Neuroimmunol. 81, 66-75.
83. Löscher, W., Honack, D., Fassbender, C.P. & Nolting, B. (1991) The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models. Epilepsy Res. 8, 171-189.
84. Lothman, E.W. & Bertram, E.H. (1993) Epileptogenic effects of status epilepticus. Epilepsia. 34 (Suppl), 1:S59-70.
85. Machida, H., Ikeda, T. & Ashida, N. (1990) Comparison of antiviral efficacies of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (brovavir) and acyclovir against herpes simplex virus type 1 infections in mice. Antiviral Res. 14, 99-107.
86. Madison, D.V., Lancaster, B. & Nicoll, R.A. (1987) Voltage clamp analysis of cholinergic action in the hippocampus. J. Neurosci. 7, 733-741.
87. Madison, D.V. & Nicoll, R.A. (1982) Noradrenaline blocks accommodation of pyramidal cell discharge in the hippocampus. Nature 299, 636-638.
88. Madison, D.V. & Nicoll, R.A. (1984) Control of the repetitive discharge of rat CA 1 pyramidal neurons in vitro. J. Physiol. 354, 319-331.
89. Margolis, T.P., Sedarati, F., Dobson, A.T., Feldman, L.T. & Stevens, J.G. (1992) Pathways of viral gene expression during acute neuronal infection with HSV-1. Virology 189, 150-160.
90. Marks, D.A., Kim, J., Spencer, D.D. & Spencer, S.S. (1992) Characteristics of intractable seizures following meningitis and encephalitis. Neurology 42, 1513-1518.
91. Mathern, G.W., Cifuentes, F., Leite, J.P., Pretorius, J.K. & Babb, T.L. (1993) Hippocampal EEG excitability and chronic spontaneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocampal kainate model. Electroencephalogr Clin Neurophysiol. 87, 326-339.
92. Mathern, G.W., Babb, T.L., Leite, J.P., Pretorius, K., Yeoman, K.M. & Kuhlman, P.A. (1996) The pathogenic and progressive features of chronic human hippocampal epilepsy. Epilepsy Res. 26, 151-161.
93. Mayer, M.L. (1986) Selective block of inward but not outward rectification in rat sensory neurones infected with herpes simplex virus. J. Physiol. 75, 327-38.
94. McGrath, N., Anderson, N.E., Croxson, M.C. & Powell, K.F. (1997) Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome. J. Neurol. Neurosurg. Psychiatry 63, 321-326.
95. McIntyre, D.C. & Plant, J.R. (1993) Long-lasting changes in the origin of spontaneous discharges from amygdala-kindled rats: piriform vs. perirhinal cortex in vitro. Brain Res. 624, 268-276.
96. Mello, L.E., Cavalheiro, E.A., Tan, A.M., Kupfer, W.R., Pretorius, J.K., Babb, T.L. & Finch, D.M. (1993) Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting. Epilepsia 34, 985-995.
97. Nadler, J.V., Perry, B.W. & Cotman, C.W. (1978) Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells. Nature 271, 676-677.
98. Naesens, L. & De Clercq, E. (2001) Recent developments in herpesvirus therapy. Herpes 8, 12-16.
99. Olson, L.C., Buescher, E.L., Artenstein, M.S. & Parkman, P.D. (1967) Herpesvirus infections of the human central nervous system. N. Engl. J. Med. 277, 1271-1277.
100. Openshaw, H., Asher, L.V,. Wohlenberg, C., Sekizawa, T. & Notkins, A.L. (1979) Acute and latent infection of sensory ganglia with herpes simplex virus: immune control and virus reactivation. J Gen Virol. 44, 205-215.
101. Park, N.H., Pavan-Langston, D. & McLean, S.L. (1979) Acylovir in oral and ganglionic herpes simplex virus infections. J. Infect. Dis. 140, 802-806.
102. Pena, Y.M., el-Mallakh, R.S., Shanley, J.D. & Podurgiel, B.J. (1987) Periodic sharp complexes in herpes simplex virus encephalitis: survival in an elderly man. Clin. Electroencephalogr. 18, 1-9.
103. Piredda, S. & Gale, K. (1985) A crucial epileptogenic site in the deep prepiriform cortex. Nature 317, 623-625.
104. Pisa, M., Sanberg, P.R., Corcoran, M.E. & Fibiger, H.C. (1980) Spontaneously recurrent seizures after intracerebral injections of kainic acid in rat: a possible model of human temporal lobe epilepsy. Brain Res. 200, 481-487.
105. Quinn, J.P., Dalziel, R.G. & Nash, A.A. (2000) Herpes virus latency in sensory ganglia – a comparison with endogenous neuronal gene expression. Progress in neurobio. 60, 167-179.
106. Racine, R.J. (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr. Clin. Neurophysiol. 32, 281-294.
107. Raschilas, F., Wolff, M., Delatour, F., Chaffaut, C., de Broucker, T., Chevret, S., Lebon, P., Canton, P. & Rozenberg, F. (2002) Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin. Infect. Dis. 35, 254-260.
108. Reiner, P.B. & Kamondi, A. (1994) Mechanisms of antihistamine-induced sedation in the human brain: H1 receptor activation reduces a background leakage potassium current. Neuroscience 59, 79-588.
109. Ribak, C.E. (1986) Contemporary methods in neurocytology and their application to the study of epilepsy. Adv Neurol. 44:739-764.
110. Rocca, W.A., Sharbrough, F.W., Hauser,W.A., Annegers, J.F. & Schoenberg, B.S. (1987) Risk factors of complex partial seizures: a population-based case-control study. Ann. Neurol. 21, 22-31.
111. Roizman, B. & Sears, A.E. (1987) An inquiry into the mechanisms of herpes simplex virus latency. Annu Rev Microbiol. 41, 543-571.
112. Roizman, B. & Furlong, D. (1974) The replication of herpesviruses. In: Fraenkel-Conart, H. & Wagner, R.R. eds. Comprehensive virology. New York: Plenum Press; 229-403.
113. Ross, C.A. (1972) Herpes simplex and temporal lobe epilepsy. Br. Med. J. 3, 112.
114. Rowley, A.H., Whitley, R.J., Lakeman, F.D. & Wolinsky, S.M. (1990) Rapid detection of herpes simplex virus DNA in CSF of patients with herpes simplex encephalitis. Lancet 335, 440-444.
115. Sanders, V.J., Felisan, S.L., Waddell, A.E., Conrad, A.J., Schmid, P., Swartz, B.E., Kaufman, M., Walsh, G.O., De Salles, A.A.F. & Tourtellotte, W.W. (1997) Presence of herpes simplex DNA in surgical tissue from human epileptic seizure foci detected by polymerase chain reaction: preliminary study. Arch. Neurol. 54, 954-960.
116. Schlitt, M., Bucher, A.P., Stroop, W.G., Pindak, F., Bastian, F.O., Jennings, R.A., Lakeman, A.D. & Whitley, R.J. (1988) Neurovirulence in an experimental focal herpes encephalitis: relationship to observed seizures. Brain Res. 440, 293-298.
117. Schmutzhard, E. (2001) Viral infections of the CNS with special emphasis on herpes simplex infections. J. Neurol. 248, 469-477.
118. Shaw, M.M., Gurr, W.K., Thackray, A.M., Watts, P.A., Littler, E. & Field, H.J. (2002) Temporal pattern of herpes simplex virus type 1 infection and cell death in the mouse brain stem: influence of guanosine nucleoside analogues. J Virol Methods. 102, 93-102.
119. Smith, D.C., Krahl, S.E., Browning, R.A. & Barea, E.J. (1993) Rapid cessation of focally induced generalized seizures in rats through microinfusion of lidocaine hydrochloride into the focus. Epilepsia 34, 43-53.
120. Sperk, G.. (1994) Kainic acid seizures in the rat. Prog Neurobiol. 42, 1-32.
121. Sperk, G., Lassmann, H., Baran, H., Seitelberger, F. & Hornykiewicz, O. (1985) Kainic acid-induced seizures: dose-relationship of behavioural, neurochemical and histopathological changes. Brain Res. 338, 289-295.
122. Speck, P.G. & Simmons, A. (1991) Divergent molecular pathways of productive and atent infection with a virulent strain of herpes simplex virus type 1. J Virol. 65, 4001-4005. Sutula, T., Cascino, G., Cavazos, J., Parada,,I. & Ramirez, L.(1989) Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann. Neurol. 26, 321-30.
123. Steiner, I. (1996) Human herpes viruses latent infection in the nervous system. Immunol Rev. 152, 157-173.
124. Stevens, J.G & Cook, M.L. (1971) Latent herpes simplex virus in spinal ganglia of mice. Science 73, 843-845.
125. Storm, J.F. (1990) Potassium currents in hippocampal pyramidal cells. Prog. Brain. Res. 83, 61-187.
126. Stroop, W.G. & Schaefer, D.C. (1986) Production of encephalitis restricted to the temporal lobes by experimental reactivation of herpes simplex virus. J. Infect. Dis. 153, 721-731.
127. Stroop, W.G. & Schaefer, D.C. (1989) Neurovirulence of two clonally related herpes simplex virus type 1 strains in a rabbit seizure model. J. Neuropathol. Exp. Neurol. 48, 171-183.
128. Sutula, T., Cascino, G., Cavazos, J., Parada,,I., Ramirez, L., 1989. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann. Neurol. 26, 321-330.Sanabria, E.R., Su, H. & Yaari, Y. (2001) Initiation of network bursts by Ca2+-dependent intrinsic bursting in the rat pilocarpine model of temporal lobe epilepsy. J. Physiol. 532, 205-216.
129. Su, Y.H., Oakes, J.E. & Lausch, R.N. (1990) Ocular avirulence of a herpes simplex virus type 1 strain is associated with heightened sensitivity to alpha/beta interferon. J. Virol. 64, 2187-2192.
130. Tauck, D.L. & Nadler, J.V. (1985) Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J. Neurosci. 5, 1016-1022.
131. Tullo, A.B,, Shimeld, C., Blyth, W.A., & Hill, T.J. & Easty, D.L. (1982) Spread of virus and distribution of latent infection following ocular herpes simplex in the non-immune and immune mouse. J Gen Virol. 63, 95-101.
132. Tumpey, TM., Chen, S.H., Oakes, J.E. & Lausch, R.N. (1996) Neutrophil-mediated suppression of virus replication after herpes simplex virus type 1 infection of the murine cornea. J. Virol. 70, 898-904.
133. Vezzani, A., Moneta, D., Richichi, C., Aliprandi, M., Burrows, S.J., Ravizza, T., Perego, C. & De Simoni, M.G. (2002) Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis. Epilepsia 43 (Suppl), 5, s30-35.
134. Wallace, H., Shorvon, S.D. & Tallis, R. (1998) Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2,052,922 and age-specific fertility rates of women with epilepsy. Lancet 352, 1970-1973.
135. Willey, D.E,, Trousdale, M,D. & Nesburn, A.B. (1984) Reactivation of murine latent HSV infection by epinephrine iontophoresis. Invest Ophthalmol Vis Sci. 25, 945-50.
136. Whitley, R.J.(1990) Viral encephalitis. N. Engl. J. Med. 323, 242-250.
137. Whitley, R.J., Alford, C.A., Hirsch, M.S., Schooley, R.T., Luby, J.P., Aoki, F.Y., Hanley, D., Nahmias, A.J. & Soong, S.J.(1986) Vidarabine versus acyclovir therapy in herpes simplex encephalitis N Engl J Med. 314, 144-149.
138. Whitley, R.J., Lakeman, A.D., Nahmias, A. & Roizman, S. (1982) DNA restriction-enzyme analysis of herpes simplex virus isolates obtained from patients with encephalitis. N. Engl. J. Med. 307, 1060-1062.
139. Whitley, R.J., Soong, S.J., Dolin, R., Galasso, G.J., Ch'ien, L.T. & Alford, C.A. (1977) Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study. N. Engl. J. Med. 297, 289-294.
140. Whitley, R.J., Soong, S.J., Hirsch, M.S., Karchmer, A.W., Dolin, R., Galasso, G., Dunnick, J.K. & Alford, C.A. (1981) Herpes simplex encephalitis: vidarabine therapy and diagnostic problems. N. Engl. J. Med. 304, 313-318.
141. Williamson, A., Spencer, D.D. & Shepherd, G.M. (1993) Comparison between the membrane and synaptic properties of human and rodent dentate granule cells. Brain Res. 622, 194-202.
142. Wu, H.M., Huang, C.C., Li, L.H., Tsai, J.J. & Hsu, K.S. (2000) The Chinese herbal medicine Chai-Hu-Long-Ku-Mu-Li-Tan (TW-001) exerts anticonvulsant effects against different experimental models of seizure in rats. Jpn. J. Pharmacol. 82, 247-260.
143. Wu, H. M., Huang, C. C., Chen, S. H., Liang, Y. C., Tsai, J. J., Hsieh, C. L. & Hsu, K. S. (2003) Herpes simplex virus type 1 inoculation enhances hippocampal excitability and seizure susceptibility in mice. Eur. J. Neurosci. 18, 3294-3304.
144. Zawatzky, R., Gresser, I., DeMaeyer, E. & Kirchner, H. (1982) The role of interferon in the resistance of C57BL/6 mice to various doses of herpes simplex virus type 1. J. Infect. Dis. 146, 405-410.

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