PTPRT在颞叶癫痫病灶异常表达：PTPRT在难治性癫痫发病机制中的研究
摘要
目的：PTPRT主要表达在中枢神经系统中,它可以通过和细胞粘附分子作用来调节突触的形成。当PTPRT过表达时可以增加树突棘的密度,增加抑制性和兴奋性突触的数量。反之,当它被敲除后树突棘的数量则会减少,而兴奋细胞的传递也会减弱。PTPRT的这些功能这提示我们PTPRT可能在癫痫发病中起到了一定的作用,为了验证我们的推测,我们研究PTPRT在难治性颞叶癫痫患者及氯化锂-匹罗卡品(LiCl-PILO)诱导的癫痫动物模型中的表达变化,以探讨PTPRT与癫痫发病机制的关系。
方法：从重庆医科大学附属第一医院难治性癫痫脑库中随机抽取30例病人的颞叶脑组织组成实验组和并在重庆医科大学附属第一医院、重庆市第二人民医院因外伤行手术减压患者中获取10例对照颞叶脑组织作为对照组。将重庆医科大学实验动物中心提供6~8周龄健康雄性SD大鼠63只随机分成7个组,其中6组注射氯化-匹罗卡品(LiCl-PILO)诱导癫痫发生,另外1组为对照组；把6组实验组分为发作后6h,1 d,7 d,14 d,30 d,60 d,并取各组颞叶脑组织为研究对象,并与对照组比较。免疫组化,免疫荧光和western blot用于检测PTPRT在人和大鼠脑组织的实验组和对照组的表达及变化规律。
结果：在人颞叶皮质中,PTPRT主要在对照组和病例组的神经元有表达,PTPRT在难治性癫痫患者脑组织中比对照组显著升高。在对照组和实验组的大鼠颞叶脑组织中,PTPRT主要在神经元中表达。与对照组相比,PTPRT在颞叶实验组动物中的表达在癫痫发作后24h内是不断升高的,到了一周和两周后表达水平则下降,到了一月和两月后表达又在升高。
结论：通过对PTPRT在癫痫动物模型和癫痫病人颞叶脑组织表达规律的研究,结合PTPRT的功能我们推测PTPRT可能通过突触的重构以及苔藓纤维的出芽参与了神经网络的重构,从而导致了难治性癫痫的发生。
Objectives:PTPRT is mainly expressed in the central nervous system. PTPRT can regulates synapse formation by interacting with cell adhesion molecules. Overexpressed of PTPRT increased the density of dendritic spines and excitatory and inhibitory synapses. Conversely, knockdown of PTPRT resulted in decrease in the number of dendritic spines and excitatory synaptic transmission. The function of PTPRT indicates it may play a role in the epilepsy. In order to verify our speculation, we investigate the expression changes of the PTPRT in temporal lobe epileptic foci from the experiment animal and epileptic patients and to approach the relationship between PTPRT and epileptogenesis.
Methods:We acquired randomly 30 temporal lobe tissue from the brain tissue of intractable epilepsy patients collected by the first affiliated hospital of Chongqing medical college, then acquired 10 temporal lobe tissue from trauma surgery patients which composed the control group. Sixty-three healthy 6-8 years SD rats provided by the experimental animal center of Chongqing university were divided to seven groups, six groups were injected lithium -pilocarpine and obtained epilepsy, the other one was control group. The six experiment groups respectively contained 9 rats at 6h,1d,7d,14d,30d,60d days post-seizure. We get the epilepsy lobe tissue from the experiment and control groups as research objects, using the immunohistochemistry, immunofluorescence and Western blot analysis to assess the expression of PTPRT and its changes.
Results:In the temporal lobe tissue of intractable patients and control groups, PTPRT was mainly expressed in the neurons. PTPRT significantly increased in intractable epilepsy patients than the control group. PTPRT was mainly expressed in the neurons in the temporal lobe brain tissue of the rats in the control group and experiment groups. Compared with control groups, PTPRT expression in the temporal lobe tissue was rising within 24h post-seizure, and decreased 1 and 2 weeks post-seizure, then it is on the rise 1 and 2 months post-seizure.
Conlusions:Through researches on the PTPRT expression in the temporal lobe brain tissue in the intractable epilepsy patients and animal models, together with the function of PTPRT, we presume that the PTPRT play a role in the synapses reorganization and moss fiber sprouting, participating in the reconstruction of the neural network which led to the intractable epilepsy.
方法：从重庆医科大学附属第一医院难治性癫痫脑库中随机抽取30例病人的颞叶脑组织组成实验组和并在重庆医科大学附属第一医院、重庆市第二人民医院因外伤行手术减压患者中获取10例对照颞叶脑组织作为对照组。将重庆医科大学实验动物中心提供6~8周龄健康雄性SD大鼠63只随机分成7个组,其中6组注射氯化-匹罗卡品(LiCl-PILO)诱导癫痫发生,另外1组为对照组；把6组实验组分为发作后6h,1 d,7 d,14 d,30 d,60 d,并取各组颞叶脑组织为研究对象,并与对照组比较。免疫组化,免疫荧光和western blot用于检测PTPRT在人和大鼠脑组织的实验组和对照组的表达及变化规律。
结果：在人颞叶皮质中,PTPRT主要在对照组和病例组的神经元有表达,PTPRT在难治性癫痫患者脑组织中比对照组显著升高。在对照组和实验组的大鼠颞叶脑组织中,PTPRT主要在神经元中表达。与对照组相比,PTPRT在颞叶实验组动物中的表达在癫痫发作后24h内是不断升高的,到了一周和两周后表达水平则下降,到了一月和两月后表达又在升高。
结论：通过对PTPRT在癫痫动物模型和癫痫病人颞叶脑组织表达规律的研究,结合PTPRT的功能我们推测PTPRT可能通过突触的重构以及苔藓纤维的出芽参与了神经网络的重构,从而导致了难治性癫痫的发生。
Objectives:PTPRT is mainly expressed in the central nervous system. PTPRT can regulates synapse formation by interacting with cell adhesion molecules. Overexpressed of PTPRT increased the density of dendritic spines and excitatory and inhibitory synapses. Conversely, knockdown of PTPRT resulted in decrease in the number of dendritic spines and excitatory synaptic transmission. The function of PTPRT indicates it may play a role in the epilepsy. In order to verify our speculation, we investigate the expression changes of the PTPRT in temporal lobe epileptic foci from the experiment animal and epileptic patients and to approach the relationship between PTPRT and epileptogenesis.
Methods:We acquired randomly 30 temporal lobe tissue from the brain tissue of intractable epilepsy patients collected by the first affiliated hospital of Chongqing medical college, then acquired 10 temporal lobe tissue from trauma surgery patients which composed the control group. Sixty-three healthy 6-8 years SD rats provided by the experimental animal center of Chongqing university were divided to seven groups, six groups were injected lithium -pilocarpine and obtained epilepsy, the other one was control group. The six experiment groups respectively contained 9 rats at 6h,1d,7d,14d,30d,60d days post-seizure. We get the epilepsy lobe tissue from the experiment and control groups as research objects, using the immunohistochemistry, immunofluorescence and Western blot analysis to assess the expression of PTPRT and its changes.
Results:In the temporal lobe tissue of intractable patients and control groups, PTPRT was mainly expressed in the neurons. PTPRT significantly increased in intractable epilepsy patients than the control group. PTPRT was mainly expressed in the neurons in the temporal lobe brain tissue of the rats in the control group and experiment groups. Compared with control groups, PTPRT expression in the temporal lobe tissue was rising within 24h post-seizure, and decreased 1 and 2 weeks post-seizure, then it is on the rise 1 and 2 months post-seizure.
Conlusions:Through researches on the PTPRT expression in the temporal lobe brain tissue in the intractable epilepsy patients and animal models, together with the function of PTPRT, we presume that the PTPRT play a role in the synapses reorganization and moss fiber sprouting, participating in the reconstruction of the neural network which led to the intractable epilepsy.
引文
1.Chapell,R., Reston,J., Snyder,D., et al. Management of treatment-resistant epilepsy. Evid Rep Technol Assess (Summ),2003.(77):1-8
2.Langan,Y., Nashef,L., Sander,J.W. Case-control study of SUDEP. Neurology,2005. 64(7):1131-1133
3.吴逊,沈鼎烈.难治性癫痫.中华神经内科杂志,1998.31(1)：4
4. Masukawa,L.M., Uruno, K., Sperling, M., et al. The functional relationship between antidromically evoked field responses of the dentate epileptic patients and and mossy fiber reorganization in temporal lobe epileptic patients. Brain Res,1992.579(1):119-127
5. Sutula,T., Cascino, G., Cavazos,J., et al. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol,1989.26(3):321-330
6. Sutula,T., Zhang,P., Lynch,M., et al. Synaptic and axonal remodeling of mossy fibers in the hilus and supragranular region of the dentate gyrus in kainate-treated rats. J Comp Neurol,1998.390:578-594
7. Buckmaster,P.S., Dudek,F.E. Neuron loss, granule cell axon reorganization,and functional changes in the dentate gyrus of epileptic kaintate treated rats.J Comp Neurol,997.385(3):385-404
8. Leite, J.P., et al.Plasticity, synaptic strength, and epilepsy:what can we learn from ultrastructural data? Epilepsia,2005.46 Suppl 5:134-141
9.So-Hee Lim, Seok-Kyu Kwon,Myung Kyu Lee, Jeonghee Moon,et al.Synapse formation regulated by protein tyrosine phosphatase receptor T through interaction with cell adhesion molecules and Fyn.The EMBO Journal,2009.28,3564-3578
10.Anoymous.proposal for revised classification of epilepsies and epileptic syndromes.Commission on classification and terminology of the International League Against Epilepsy.Epilepsia,1989.30(4):389-399
11.Racine, R.J.Modification of seizure activity by electrical stimulation. Ⅱ. Motor seizure. Electroencephalogr Clin Neurophysiol,1972.32(3):281-94
12.吕晓明,高旭光,刘芳.锂一匹罗卡品致病幼鼠海马结构损伤的形态学及苔鲜纤维芽生研究.中国临床神经科学杂志,2002.10：9-12
13.Dudek,F.E., Spitz ,M. Hypothetical mechanisms for the cellular and neurophysiologic basis of secondary epileptogenesis:proposed role of synaptic reorganization. J Clin Neurophysiol,1997.14: 90-101
14. Shibley, H., Smith,B.N. Pilocarpine-induced status epilepticus results in mossy fiber sprouting and spontaneous seizures in C57BL/6 and CD-1 mice. Epilepsy Res,2002.49(2): 109-120
15. Tauck, D.L, Nadler, J.V. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J Neurosci,1985.5(4):1016-1022
16.Cronin,J., Dudek,F.E. Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res,1988.474:181-184
17.Cronin,J., Obenaus,A., et al. Electrophysiology of dentate granule cells after kainite-induced synaptic reorganization of the mossy fibers. Brain Res,1992.573:305-310
18.Lynch,M., Sutula, T. Recurrent excitatory connectivity in the dentate gyrus of kindled and kainic acid-treated rats. J Neurophysiol,2000.83:693-704
19.Winokur,R.S., Kubal, T., et al. Recurrent excitation in the dentate gyrus of a murine model of temporal lobe epilepsy. Epilepsy Res,2004.58:93-105
20.Wuarin,J.P., Dudek,F,E. Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rat,1996. J Neurosci 16: 4438-4448
21.Wuarin,J.P., Dudek, F.E. Excitatory synaptic input to granule cells increases with time after kainate treatment. J Neurophysiol,2001.85:1067-1077
22.Hamani,C.,Mello,L. E.Spontaneous recurrent seizures and neuropathology in the chronic Phase of the Pilocarpine and Picrotoxin model epilepsy.Neurol.Res,2002.2(4):199-209
23. Dalva, M. B., McClelland, A. C., and Kayser, M. S.Cell adhesion molecules:signalling functions at the synapse. Nat. Rev. Neurosci,2007.8(3),206-220
24. Biederer, T., and Stagi, M. Signaling by synaptogenic molecules. Curr. Opin. Neurobiol,2008. 18,261-269
25. Bruse's, J. L. N-cadherin signaling in synapse formation and neuronal physiology. Mol. Neurobiol,2006.33,237-252
26. Craig, A. M., Kang, Y.Neurexin-neuroligin signaling in synapse development. Curr. Opin. Neurobiol,2007.17,43-52
27.Besco, J., Popesco, M.C., Davuluri, R.V., Frostthlm, A., Rotter A. Genomic structure and alternative splicing of murine R2B receptor protein tyrosine phosphatases (PTPk, m, r and PCP-2). BMC Genomics,2004.5:14-32
28.Alonso, A., Sasin,J., Bottini, N., Friedberg,I., Osterman A., Godzik A.,Hunter T., Dixon J., Mustelin T.Protein tyrosine phosphatases in the human genome. Cell,2004.117:699-711
29.Besco, J., Huijsduijnen, R., Frostholm, A., Rotter, A.Intracellular substrates of brain-enriched receptor protein tyrosine phosphatase rho (RPTPr/PTPRT). Brain Res,2006.1116:50-57
30. Besco, J.A., Hooft van Huijsduijnen,R., Frostholm, A., Rotter, A.Intracellular substrates of brain-enriched receptor protein tyrosine phosphatase rho (RPTPrho/PTPRT).Brain Res.,2006.Oct 20;1116(1):50-7
31.Ichtchenko, K., Hata, Y., Nguyen, T., et al. Neuroligin 1:a splice site-specific ligand for beta-neurexins. Cell 1995.81,435-443
32. Biederer, T.& Sudhof, T. C. Direct binding to neurexins and recruitment of munc18.J. Biol. Chem,2000.275,39803-39806
33.Varoqueaux, F., Jamain, S., Brose, N..Neuroligin 2 is exclusively localized to inhibitory synapses.Eur J Cell Biol,2004.Sep;83(9):449-456
34.Levinson, J. N., Che'ry, N., Huang, K., Wong, T. P., Gerrow, K., Kang, R., Prange, O., Wang, Y. T., and El-Husseini, A. Neuroligins mediate excitatory and inhibitory synapse formation: involvement of PSD-95 and neurexin-lbeta in neuroligin-induced synaptic specificity. J. Biol. Chem,2005.280,17312-17319
35.Song, J. Y., Ichtchenko, K.,Sudhof, T. C., Brose, N.Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc.Natl. Acad. Sci.,1999.U.S.A.96,1100-1105
36.Varoqueaux, F., Aramuni, G., Rawson, R. L., Mohrmann, R., Missler, M., Gottmann, K., Zhang, W., Sudhof T. C., Brose, N.Neuroligins determine synapse maturation and function. Neuron,2006.51,741-754
37.Chih, B., Engelman, H., Scheiffele, P.Control of excitatory and inhibitory synapse formation by neuroligins. Science,2005.307,1324-1328
38.Prange, O., Wong, T. P., Gerrow, K., Wang, Y. T., El-Husseini, A.A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin. Proc. Natl. Acad. Sci.,2004.101,13915-13920
39.Chubykin, A. A., Liu, X., Comoletti, D., Tsigelny, I., et al. Dissection of synapse induction by neuroligins:effect of a neuroligin mutation associated with autism.J. Biol. Chem.,2005.280(23), 22365-22374
40. Koch, A. W., Pokutta, S., Lustig, A.,Engel, J. Calcium binding and homoassociation of E-cadherin domains.Biochemistry,1997.36,7697-7705
41.Fannon, A. M., and Colman, D. R.A model for central synaptic junctional complex formation based on the differential adhesive specificities of the cadherins. Neuron,1996.17,423-434
42.Uchida, N., Honjo, Y., Johnson, K. R., et al.The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones. J. Cell Biol.,1996.135,767-779
43.Benson, D. L., Tanaka, H. N-cadherin redistribution during synaptogenesis in hippocampal neurons. J. Neurosci.,1998.18,6892-6904
44.Togashi, H., Abe, K., et al. Cadherin regulates dendritic spine morphogenesis. Neuron,2002.35, 77-89
45. Bozdagi, O., Valcin, M., Poskanzer, K., et al.Temporally distinct demands for classic cadherins in synapse formation and maturation. Mol. Cell. Neurosci.,2004.27,509-521
46. Saglietti, L., Dequidt, C., Kamieniarz, K., Rousset, M. C., et al.Extracellular interactions between GluR2 and N-cadherin in spine regulation. Neuron,2007.54,461-477
47. Bamji, S. X., Shimazu, K., Kimes, N., Huelsken, J., et al. Role of beta-catenin in synaptic vesicle localization and presynaptic assembly. Neuron,2003.40,719-731
48. Latefi, N. S., Pedraza, L., Schohl, A., Li, Z., Ruthazer, E. S. N-cadherin prodomain cleavage regulates synapse formation in vivo. Dev. Neurobiol,2009.69,518-529
49. Murase, S., Mosser, E.,Schuman, E. M.Depolarization drives β-Catenin into neuronal spines promoting changes in synaptic structure and function. Neuron,2002.35,91-105
50.Treubert Zimmermann,U., Heyers, D., Redies, C.Targeting axons to specific fiber tracts in vivo by altering cadherin expression. J Neurosei,2002.22:7617—7626
51. Stan, A., Pielarski, K. N., Brigadski, T., et al. Essential cooperation of N-cadherin and neuroligin-1 in the transsynaptic control of vesicle accumulation.Proc. Natl.Acad. Sci. U.S.A.,2010.107,11116-11121
52. Nishimura, W., Yao, I., Iida,J., Tanaka, N., Hata,Y. Interaction of synaptic scaffolding molecule and Beta -catenin. J. Neurosci,2002.22,757-765
53. Iida, J., Hirabayashi., S, Sato, Y., Hata,Y. Synaptic scaffolding molecule is involved in the synaptic clustering of neuroligin. Mol. Cell. Neurosci,2004.27,497-508
54. Shan,W., Yoshida,M., et al.Neural (N-) cadherin, a synaptic adhesion molecule, is induced in hippocampal mossy fiber axonal sprouts by seizure. J Neurosci Res,2002.69(3):292-304
55. Fujita,M., Aihara,N., Yamamoto, M., et al.Regulation of rat hippocampal neural cadherin in the kainic acid induced seizures. Neurosci Lett,2001.5;297(1):13-6
56. Jean-Pierre Wuarin,et al. Excitatory Synaptic Input to Granule Cells Increases With Time After Kainate TreatmentJ Neurophysiol,2001.85:1067-1077
1. Siegel AM. Presurgical evaluation and surgical treatment of medically refractory epilepsy. Neurosurg Rev,2004; 27:1-18.
2.吴逊,沈鼎烈.难治性癫痫.中华神经内科杂志,1998,31(1)：4.
3. Murray MI, Halpern MT, Leppik IE. Cost of refractory epilepsy in adults in the USA. Epilepsy Res,1996;23:139-148.
4. Jacoby A, Buck D, Baker G, McNamee P, Graham-Jones S, Chadwick D. Uptake and costs of care for epilepsy:findings from a U.K. regional study. Epilepsia,1998;39:776-786.
5. Chapell R, Reston J, Snyder D, Treadwell J, Treager S, Turkelson C. Management of treatment-resistant epilepsy. Evid Rep Technol Assess (Summ),2003 Apr;(77):1-8.
6. Langan Y, Nashef L, Sander JW. Case-control study of SUDEP. Neurology,2005; 64:1131-1133.
7. Sperling MR, Feldman H, Kinman J, Liporace JD,O'Connor MJ. Seizure control and mortality in epilepsy.Ann Neurol,1999; 46:45-50.
8. Perucca E. Pharmacoresistance in epilepsy:how should it be defined? CNS Drugs,1998; 10:171-179.
9. Gumnit RJ, Walczak TS; National Association of Epilepsy Centers. Guidelines for essential services, personnel,and facilities in specialized epilepsy centers in the United States. Epilepsia,2001; 42:804-814.
10. Smith D, Defalla BA, Chadwick DW. The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. QJM,1999; 92:15-23.
11. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med,2000; 342:314-319.
12. Regesta G, Tanganelli P. Clinical aspects and biological bases of drug-resistant epilepsies. Epilepsy Res,1999; 34:109-122.
13. Berg AT, Langfitt J, Shinnar S, et al. How long does it take for partial epilepsy to become intractable? Neurology,2003; 60:186-190.
14. Loscher W, Schmidt D. Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs. Epilepsia,2006;47:1253-1284.
15. Loscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci,2005; 6:591-602.
16. Oby E, Janigro D. The blood-brain barrier and epilepsy. Epilepsia,2006; 47:1761-1774.
17. Remy S, Beck H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain,2006; 129:18-35.
18. Loscher W, Schmidt D.New horizons in the development of antiepileptic drugs. Epilepsy Res, 2002;50:3-16.
19.BalIaban-Gil K,Callahan C,O'DELL C,et al.Complications of the ketogenic diet.Epilepsia,1998;39(7):744-748.
20. Zumsteg D, Jenny D, Wieser HG. Vocal cord adduction during vagus nerve stimulation for treatment of epilepsy. Neurology,2000;54 (2):1388-1389.
21.Labar D. Vagus nerve stimulation for intractable epilepsy in children.Dev Med Child Neurolo, 2000;42(7):496-499.
22.Engel JJR, Ojemann GA. The next step. In:Engel JJR(ed). Surgical treatment of the epilepsies.2ed [J]. New york:Raven Press,1992;319-329.
23. Wiebe S, Blume WT, Girvin JP, Eliasziw M.Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med,2001; 345:311-318.
24.Bourgeois M, Sainte RC, Lellouch TA, et al. Surgery of epilepsyassociated with focal lesions in childhood. Neurosurg,1999;90(5):833-842.
25. Asadi-Pooya AA, Sharan A, Nei M, Sperling MR. Corpus callosotomy. Epilepsy Behav,2008; 13:271-278.
26.Liu ZH, Zhao QJ, Li SY, et al. Multiple subpial transection for treatment of intractable epilepsy. Chin Med J,1995;108:539-541.
27. Spencer SS, Schramm J,Wyler A,et al. Mutiple subpial transaction for intractable partial epilepsy:an international meta-analysis. Epilepsia,2002;43(2):141-145.
28. Detlev B. Cell and gene therapies for refractory epilepsy. Curr Neuropharmacol,2007; 5:115-125.
2.Langan,Y., Nashef,L., Sander,J.W. Case-control study of SUDEP. Neurology,2005. 64(7):1131-1133
3.吴逊,沈鼎烈.难治性癫痫.中华神经内科杂志,1998.31(1)：4
4. Masukawa,L.M., Uruno, K., Sperling, M., et al. The functional relationship between antidromically evoked field responses of the dentate epileptic patients and and mossy fiber reorganization in temporal lobe epileptic patients. Brain Res,1992.579(1):119-127
5. Sutula,T., Cascino, G., Cavazos,J., et al. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol,1989.26(3):321-330
6. Sutula,T., Zhang,P., Lynch,M., et al. Synaptic and axonal remodeling of mossy fibers in the hilus and supragranular region of the dentate gyrus in kainate-treated rats. J Comp Neurol,1998.390:578-594
7. Buckmaster,P.S., Dudek,F.E. Neuron loss, granule cell axon reorganization,and functional changes in the dentate gyrus of epileptic kaintate treated rats.J Comp Neurol,997.385(3):385-404
8. Leite, J.P., et al.Plasticity, synaptic strength, and epilepsy:what can we learn from ultrastructural data? Epilepsia,2005.46 Suppl 5:134-141
9.So-Hee Lim, Seok-Kyu Kwon,Myung Kyu Lee, Jeonghee Moon,et al.Synapse formation regulated by protein tyrosine phosphatase receptor T through interaction with cell adhesion molecules and Fyn.The EMBO Journal,2009.28,3564-3578
10.Anoymous.proposal for revised classification of epilepsies and epileptic syndromes.Commission on classification and terminology of the International League Against Epilepsy.Epilepsia,1989.30(4):389-399
11.Racine, R.J.Modification of seizure activity by electrical stimulation. Ⅱ. Motor seizure. Electroencephalogr Clin Neurophysiol,1972.32(3):281-94
12.吕晓明,高旭光,刘芳.锂一匹罗卡品致病幼鼠海马结构损伤的形态学及苔鲜纤维芽生研究.中国临床神经科学杂志,2002.10：9-12
13.Dudek,F.E., Spitz ,M. Hypothetical mechanisms for the cellular and neurophysiologic basis of secondary epileptogenesis:proposed role of synaptic reorganization. J Clin Neurophysiol,1997.14: 90-101
14. Shibley, H., Smith,B.N. Pilocarpine-induced status epilepticus results in mossy fiber sprouting and spontaneous seizures in C57BL/6 and CD-1 mice. Epilepsy Res,2002.49(2): 109-120
15. Tauck, D.L, Nadler, J.V. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J Neurosci,1985.5(4):1016-1022
16.Cronin,J., Dudek,F.E. Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res,1988.474:181-184
17.Cronin,J., Obenaus,A., et al. Electrophysiology of dentate granule cells after kainite-induced synaptic reorganization of the mossy fibers. Brain Res,1992.573:305-310
18.Lynch,M., Sutula, T. Recurrent excitatory connectivity in the dentate gyrus of kindled and kainic acid-treated rats. J Neurophysiol,2000.83:693-704
19.Winokur,R.S., Kubal, T., et al. Recurrent excitation in the dentate gyrus of a murine model of temporal lobe epilepsy. Epilepsy Res,2004.58:93-105
20.Wuarin,J.P., Dudek,F,E. Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rat,1996. J Neurosci 16: 4438-4448
21.Wuarin,J.P., Dudek, F.E. Excitatory synaptic input to granule cells increases with time after kainate treatment. J Neurophysiol,2001.85:1067-1077
22.Hamani,C.,Mello,L. E.Spontaneous recurrent seizures and neuropathology in the chronic Phase of the Pilocarpine and Picrotoxin model epilepsy.Neurol.Res,2002.2(4):199-209
23. Dalva, M. B., McClelland, A. C., and Kayser, M. S.Cell adhesion molecules:signalling functions at the synapse. Nat. Rev. Neurosci,2007.8(3),206-220
24. Biederer, T., and Stagi, M. Signaling by synaptogenic molecules. Curr. Opin. Neurobiol,2008. 18,261-269
25. Bruse's, J. L. N-cadherin signaling in synapse formation and neuronal physiology. Mol. Neurobiol,2006.33,237-252
26. Craig, A. M., Kang, Y.Neurexin-neuroligin signaling in synapse development. Curr. Opin. Neurobiol,2007.17,43-52
27.Besco, J., Popesco, M.C., Davuluri, R.V., Frostthlm, A., Rotter A. Genomic structure and alternative splicing of murine R2B receptor protein tyrosine phosphatases (PTPk, m, r and PCP-2). BMC Genomics,2004.5:14-32
28.Alonso, A., Sasin,J., Bottini, N., Friedberg,I., Osterman A., Godzik A.,Hunter T., Dixon J., Mustelin T.Protein tyrosine phosphatases in the human genome. Cell,2004.117:699-711
29.Besco, J., Huijsduijnen, R., Frostholm, A., Rotter, A.Intracellular substrates of brain-enriched receptor protein tyrosine phosphatase rho (RPTPr/PTPRT). Brain Res,2006.1116:50-57
30. Besco, J.A., Hooft van Huijsduijnen,R., Frostholm, A., Rotter, A.Intracellular substrates of brain-enriched receptor protein tyrosine phosphatase rho (RPTPrho/PTPRT).Brain Res.,2006.Oct 20;1116(1):50-7
31.Ichtchenko, K., Hata, Y., Nguyen, T., et al. Neuroligin 1:a splice site-specific ligand for beta-neurexins. Cell 1995.81,435-443
32. Biederer, T.& Sudhof, T. C. Direct binding to neurexins and recruitment of munc18.J. Biol. Chem,2000.275,39803-39806
33.Varoqueaux, F., Jamain, S., Brose, N..Neuroligin 2 is exclusively localized to inhibitory synapses.Eur J Cell Biol,2004.Sep;83(9):449-456
34.Levinson, J. N., Che'ry, N., Huang, K., Wong, T. P., Gerrow, K., Kang, R., Prange, O., Wang, Y. T., and El-Husseini, A. Neuroligins mediate excitatory and inhibitory synapse formation: involvement of PSD-95 and neurexin-lbeta in neuroligin-induced synaptic specificity. J. Biol. Chem,2005.280,17312-17319
35.Song, J. Y., Ichtchenko, K.,Sudhof, T. C., Brose, N.Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc.Natl. Acad. Sci.,1999.U.S.A.96,1100-1105
36.Varoqueaux, F., Aramuni, G., Rawson, R. L., Mohrmann, R., Missler, M., Gottmann, K., Zhang, W., Sudhof T. C., Brose, N.Neuroligins determine synapse maturation and function. Neuron,2006.51,741-754
37.Chih, B., Engelman, H., Scheiffele, P.Control of excitatory and inhibitory synapse formation by neuroligins. Science,2005.307,1324-1328
38.Prange, O., Wong, T. P., Gerrow, K., Wang, Y. T., El-Husseini, A.A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin. Proc. Natl. Acad. Sci.,2004.101,13915-13920
39.Chubykin, A. A., Liu, X., Comoletti, D., Tsigelny, I., et al. Dissection of synapse induction by neuroligins:effect of a neuroligin mutation associated with autism.J. Biol. Chem.,2005.280(23), 22365-22374
40. Koch, A. W., Pokutta, S., Lustig, A.,Engel, J. Calcium binding and homoassociation of E-cadherin domains.Biochemistry,1997.36,7697-7705
41.Fannon, A. M., and Colman, D. R.A model for central synaptic junctional complex formation based on the differential adhesive specificities of the cadherins. Neuron,1996.17,423-434
42.Uchida, N., Honjo, Y., Johnson, K. R., et al.The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones. J. Cell Biol.,1996.135,767-779
43.Benson, D. L., Tanaka, H. N-cadherin redistribution during synaptogenesis in hippocampal neurons. J. Neurosci.,1998.18,6892-6904
44.Togashi, H., Abe, K., et al. Cadherin regulates dendritic spine morphogenesis. Neuron,2002.35, 77-89
45. Bozdagi, O., Valcin, M., Poskanzer, K., et al.Temporally distinct demands for classic cadherins in synapse formation and maturation. Mol. Cell. Neurosci.,2004.27,509-521
46. Saglietti, L., Dequidt, C., Kamieniarz, K., Rousset, M. C., et al.Extracellular interactions between GluR2 and N-cadherin in spine regulation. Neuron,2007.54,461-477
47. Bamji, S. X., Shimazu, K., Kimes, N., Huelsken, J., et al. Role of beta-catenin in synaptic vesicle localization and presynaptic assembly. Neuron,2003.40,719-731
48. Latefi, N. S., Pedraza, L., Schohl, A., Li, Z., Ruthazer, E. S. N-cadherin prodomain cleavage regulates synapse formation in vivo. Dev. Neurobiol,2009.69,518-529
49. Murase, S., Mosser, E.,Schuman, E. M.Depolarization drives β-Catenin into neuronal spines promoting changes in synaptic structure and function. Neuron,2002.35,91-105
50.Treubert Zimmermann,U., Heyers, D., Redies, C.Targeting axons to specific fiber tracts in vivo by altering cadherin expression. J Neurosei,2002.22:7617—7626
51. Stan, A., Pielarski, K. N., Brigadski, T., et al. Essential cooperation of N-cadherin and neuroligin-1 in the transsynaptic control of vesicle accumulation.Proc. Natl.Acad. Sci. U.S.A.,2010.107,11116-11121
52. Nishimura, W., Yao, I., Iida,J., Tanaka, N., Hata,Y. Interaction of synaptic scaffolding molecule and Beta -catenin. J. Neurosci,2002.22,757-765
53. Iida, J., Hirabayashi., S, Sato, Y., Hata,Y. Synaptic scaffolding molecule is involved in the synaptic clustering of neuroligin. Mol. Cell. Neurosci,2004.27,497-508
54. Shan,W., Yoshida,M., et al.Neural (N-) cadherin, a synaptic adhesion molecule, is induced in hippocampal mossy fiber axonal sprouts by seizure. J Neurosci Res,2002.69(3):292-304
55. Fujita,M., Aihara,N., Yamamoto, M., et al.Regulation of rat hippocampal neural cadherin in the kainic acid induced seizures. Neurosci Lett,2001.5;297(1):13-6
56. Jean-Pierre Wuarin,et al. Excitatory Synaptic Input to Granule Cells Increases With Time After Kainate TreatmentJ Neurophysiol,2001.85:1067-1077
1. Siegel AM. Presurgical evaluation and surgical treatment of medically refractory epilepsy. Neurosurg Rev,2004; 27:1-18.
2.吴逊,沈鼎烈.难治性癫痫.中华神经内科杂志,1998,31(1)：4.
3. Murray MI, Halpern MT, Leppik IE. Cost of refractory epilepsy in adults in the USA. Epilepsy Res,1996;23:139-148.
4. Jacoby A, Buck D, Baker G, McNamee P, Graham-Jones S, Chadwick D. Uptake and costs of care for epilepsy:findings from a U.K. regional study. Epilepsia,1998;39:776-786.
5. Chapell R, Reston J, Snyder D, Treadwell J, Treager S, Turkelson C. Management of treatment-resistant epilepsy. Evid Rep Technol Assess (Summ),2003 Apr;(77):1-8.
6. Langan Y, Nashef L, Sander JW. Case-control study of SUDEP. Neurology,2005; 64:1131-1133.
7. Sperling MR, Feldman H, Kinman J, Liporace JD,O'Connor MJ. Seizure control and mortality in epilepsy.Ann Neurol,1999; 46:45-50.
8. Perucca E. Pharmacoresistance in epilepsy:how should it be defined? CNS Drugs,1998; 10:171-179.
9. Gumnit RJ, Walczak TS; National Association of Epilepsy Centers. Guidelines for essential services, personnel,and facilities in specialized epilepsy centers in the United States. Epilepsia,2001; 42:804-814.
10. Smith D, Defalla BA, Chadwick DW. The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. QJM,1999; 92:15-23.
11. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med,2000; 342:314-319.
12. Regesta G, Tanganelli P. Clinical aspects and biological bases of drug-resistant epilepsies. Epilepsy Res,1999; 34:109-122.
13. Berg AT, Langfitt J, Shinnar S, et al. How long does it take for partial epilepsy to become intractable? Neurology,2003; 60:186-190.
14. Loscher W, Schmidt D. Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs. Epilepsia,2006;47:1253-1284.
15. Loscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci,2005; 6:591-602.
16. Oby E, Janigro D. The blood-brain barrier and epilepsy. Epilepsia,2006; 47:1761-1774.
17. Remy S, Beck H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain,2006; 129:18-35.
18. Loscher W, Schmidt D.New horizons in the development of antiepileptic drugs. Epilepsy Res, 2002;50:3-16.
19.BalIaban-Gil K,Callahan C,O'DELL C,et al.Complications of the ketogenic diet.Epilepsia,1998;39(7):744-748.
20. Zumsteg D, Jenny D, Wieser HG. Vocal cord adduction during vagus nerve stimulation for treatment of epilepsy. Neurology,2000;54 (2):1388-1389.
21.Labar D. Vagus nerve stimulation for intractable epilepsy in children.Dev Med Child Neurolo, 2000;42(7):496-499.
22.Engel JJR, Ojemann GA. The next step. In:Engel JJR(ed). Surgical treatment of the epilepsies.2ed [J]. New york:Raven Press,1992;319-329.
23. Wiebe S, Blume WT, Girvin JP, Eliasziw M.Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med,2001; 345:311-318.
24.Bourgeois M, Sainte RC, Lellouch TA, et al. Surgery of epilepsyassociated with focal lesions in childhood. Neurosurg,1999;90(5):833-842.
25. Asadi-Pooya AA, Sharan A, Nei M, Sperling MR. Corpus callosotomy. Epilepsy Behav,2008; 13:271-278.
26.Liu ZH, Zhao QJ, Li SY, et al. Multiple subpial transection for treatment of intractable epilepsy. Chin Med J,1995;108:539-541.
27. Spencer SS, Schramm J,Wyler A,et al. Mutiple subpial transaction for intractable partial epilepsy:an international meta-analysis. Epilepsia,2002;43(2):141-145.
28. Detlev B. Cell and gene therapies for refractory epilepsy. Curr Neuropharmacol,2007; 5:115-125.