mTOR抑制剂抑制皮质发育不良小鼠癫痫发作_Journal of Epilepsy

Authors：

NguyenLH , BrewsterAL , ClarkME , Regnier-GolanovA , SunnenCN , PatilVV , D′ArcangeloG ,  AndersonAE , 迟潇洒 , 慕洁

Corresponding author：

AndersonAE, Email: annea@bcm.edu

Keywords：

皮质发育畸形; 癫痫; 雷帕霉素; 星形胶质细胞增生; 小胶质细胞增生

DOI：

10.7507/2096-0247.20170011

Video：

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哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)在皮质发育不良(Cortical dysplasia, CD)及癫痫动物模型中超活化。在神经元特异性Pten基因敲除(Neuronsubset-specific Pten knockout, NS-Pten KO)小鼠模型中, 尽管在早期癫痫发生过程中抑制mTOR信号通路能够减少癫痫样活动, 但mTOR抑制剂在癫痫建立后的作用尚不清楚。文章通过建立伴有严重慢性癫痫的NS-Pten KO成年小鼠模型, 探究mTOR抑制剂对其癫痫样活动和其他神经病理的作用。NS-Pten KO小鼠癫痫样活动、mTOR信号通路的异常调节和相关神经病理随年龄增长的变化通过视频脑电(video-electroencephalography, VEEG), 蛋白免疫印迹和免疫组化检测。NS-Pten KO小鼠出生后9周开始接受mTOR抑制剂雷帕霉素治疗(10 mg/kg i.p, 5d/周)并采用VEEG监测癫痫样活动。通过蛋白免疫印迹和免疫组化检测雷帕霉素的作用。试验发现, 随着年龄增长, NS-Pten KO小鼠的癫痫样活动恶化, 同时伴有mTOR复合物1和2(mTOR complex 1 and 2, mTORC1 and mTORC2)调节异常和进展性的星形胶质细胞和小胶质细胞增生。雷帕霉素治疗抑制癫痫样活动, 改善基线脑电活动并提高严重癫痫NS-PtenKO小鼠的预后。在分子水平, 雷帕霉素治疗降低mTORC1和mTORC2水平并减少星形胶质细胞和小胶质细胞增生。研究表明在NS-Pten KO小鼠中, 雷帕霉素成功治疗癫痫有较宽的时间窗。抑制mTOR可能是CD伴慢性癫痫及mTOR信号通路基因调节异常的潜在治疗手段。

Citation： NguyenLH, BrewsterAL, ClarkME, Regnier-GolanovA, SunnenCN, PatilVV, D′ArcangeloG, AndersonAE, 迟潇洒, 慕洁. mTOR抑制剂抑制皮质发育不良小鼠癫痫发作. Journal of Epilepsy, 2017, 3(1): 70-79. doi: 10.7507/2096-0247.20170011 Copy

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2.	Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell, 2012, 149(11):274-293.
3.	Orlova KA, Crino PB. The tuberous sclerosis complex. Ann N Y Acad Sci, 2010, 1184(3):87-105.
4.	Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegal encephaly. Nat Genet, 2012, 44(10):941-945.
5.	Orlova KA, Parker WE, Heuer GG, et al. STRADalpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice. J Clin Invest, 2010, 120(8):1591-1602.
6.	Puffenberger EG, Strauss KA, Ramsey KE, et al. Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5. Brain, 2007, 130(7):1929-1941.
7.	Wong M. Mammalian target of rapamycin (mTOR) pathways in neurological diseases. Biomed J, 2013, 36(2):40-50.
8.	Wong M, Crino PB. mTOR and epileptogenesis in developmental brain malformations. In Noebels JL, Avoli M, Rogawski MA, et al. (Eds) Jasper's basic mechanisms of the epilepsies. Bethesda, MD:National Center for Biotechnology Information (US), 2012.
9.	Zeng LH, Rensing NR, Wong M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neuro Sci, 2009, 29(1):6964-6972.
10.	Huang X, Zhang H, Yang J, et al. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis, 2010, 40(2):193-199.
11.	Ljungberg MC, Bhattacharjee MB, Lu Y, et al. Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol, 2006, 60(10):420-429.
12.	Aronica E, Boer K, Baybis M, et al. Co-expression of cyclin D1 and phosphorylated ribosomal S6 proteins in hemimegalencephaly. Acta Neuropathol, 2007, 114(4):287-293.
13.	Miyata H, Chiang AC, Vinters HV. Insulin signaling pathways in cortical dysplasia and TSC-tubers:tissue microarray analysis. Ann Neurol, 2004, 56(10):510-519.
14.	Baybis M, Yu J, Lee A, et al. mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann Neurol, 2004, 56(5):478-487.
15.	Sha LZ, Xing XL, Zhang D, et al. Mapping the spatio-temporal pattern of the mammalian target of rapamycin (mTOR) activation in temporal lobe epilepsy. PLoS ONE, 2012, 7(1):e39152.
16.	Sosunov AA, Wu X, McGovern RA, et al. The mTOR pathway is activated in glial cells in mesial temporal sclerosis. Epilepsia, 2012, 53(Suppl. 1):78-86.
17.	Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell, 2006, 22(9):159-168.
18.	Backman SA, Stambolic V, Suzuki A, et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet, 2001, 29(7):396-403.
19.	Kwon CH, Zhu X, Zhang J, et al. Pten regulates neuronal soma size:a mouse model of Lhermitte-Duclos disease. Nat Genet, 2001, 29(6):404-411.
20.	Ljungberg MC, Sunnen CN, Lugo JN, et al. Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech, 2009, 2(5):389-398.
21.	Sunnen CN, Brewster AL, Lugo JN, et al. Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice. Epilepsia, 2011, 52(8):2065-2075.
22.	Brewster AL, Lugo JN, Patil VV, et al. Rapamycin reverses status epilepticus-induced memory deficits and dendritic damage. PLoS ONE, 2013, 8(2):e57808.
23.	Hoeffer CA, Klann E. mTOR signaling:at the crossroads of plasticity, memory and disease. Trends Neurosci, 2010, 33(4):67-75.
24.	Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell, 2007, 12(10):9-22.
25.	Talos DM, Sun H, Zhou X, et al. The interaction between early life epilepsy and autistic-like behavioral consequences:a role for the mammalian target of rapamycin (mTOR) pathway. PLoS ONE, 2012, 7(2):e35885.
26.	Dello Russo C, Lisi L, Feinstein DL, et al. mTOR kinase, a key player in the regulation of glial functions:relevance for the therapy of multiple sclerosis. Glia, 2013, 61(7):301-311.
27.	Vezzani A, French J, Bartfai T, et al. The role of inflammation in epilepsy. Nat Rev Neurol, 2011, 7(3):31-40.
28.	Kettenmann H, Hanisch UK, Noda M, et al. Physiology of microglia. Physiol Rev, 2011, 91(7):461-553.
29.	Bajorat R, Wilde M, Sellmann T, et al. Seizure frequency in pilocarpine-treated rats is independent of circadian rhythm. Epilepsia, 2011, 52(12):e118-e122.
30.	Goffin K, Nissinen J, Van Laere K, et al. Cyclicity of spontaneous recurrent seizures in pilocarpine model of temporal lobe epilepsy in rat. Exp Neurol, 2007, 205(11):501-505.
31.	Williams PA, White AM, Clark S, et al. Development of spontaneous recurrent seizures after kainate-induced status epilepticus. J Neurosci, 2009, 29(7):2103-2112.
32.	Kadam SD, White AM, Staley KJ, et al. Continuous electroencephalographic monitoring with radio-telemetry in a rat model of perinatal hypoxia-ischemia reveals progressive post-stroke epilepsy. J Neurosci, 2010, 30(8):404-415.
33.	Lasarge CL, Danzer SC. Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation. Front Mol Neurosci, 2014, 7(3):18.
34.	Buckmaster PS, Ingram EA, Wen X. Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci, 2009, 29(7):8259-8269.
35.	Ming GL, Song H. Adult neurogenesis in the mammalian brain:significant answers and significant questions. Neuron, 2011, 70(2):687-702.
36.	Pun RY, Rolle IJ, Lasarge CL, et al. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron, 2012, 75:1022-1034.
37.	Devinsky O, Vezzani A, Najjar S, et al. Glia and epilepsy:excitability and inflammation. Trends Neurosci, 2013, 36(7):174-184.
38.	Krueger DA, Wilfong AA, Holland-Bouley K, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol, 2013, 74(5):679-687.
39.	Zeng LH, Xu L, Gutmann DH, et al. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol, 2008, 63(2):444-453.
40.	Zhou J, Blundell J, Ogawa S, et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci, 2009, 29(2):1773-1783.
41.	Hailer NP. Immunosuppression after traumatic or ischemic CNS damage:it is neuroprotective and illuminates the role of microglial cells. Prog Neurobiol, 2008, 84(3):211-233.

1. Crino PB, Chou K. Epilepsy and cortical dysplasias. Curr Treat Options Neurol, 2000, 2(5):543-552.
2. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell, 2012, 149(11):274-293.
3. Orlova KA, Crino PB. The tuberous sclerosis complex. Ann N Y Acad Sci, 2010, 1184(3):87-105.
4. Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegal encephaly. Nat Genet, 2012, 44(10):941-945.
5. Orlova KA, Parker WE, Heuer GG, et al. STRADalpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice. J Clin Invest, 2010, 120(8):1591-1602.
6. Puffenberger EG, Strauss KA, Ramsey KE, et al. Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5. Brain, 2007, 130(7):1929-1941.
7. Wong M. Mammalian target of rapamycin (mTOR) pathways in neurological diseases. Biomed J, 2013, 36(2):40-50.
8. Wong M, Crino PB. mTOR and epileptogenesis in developmental brain malformations. In Noebels JL, Avoli M, Rogawski MA, et al. (Eds) Jasper's basic mechanisms of the epilepsies. Bethesda, MD:National Center for Biotechnology Information (US), 2012.
9. Zeng LH, Rensing NR, Wong M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neuro Sci, 2009, 29(1):6964-6972.
10. Huang X, Zhang H, Yang J, et al. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis, 2010, 40(2):193-199.
11. Ljungberg MC, Bhattacharjee MB, Lu Y, et al. Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol, 2006, 60(10):420-429.
12. Aronica E, Boer K, Baybis M, et al. Co-expression of cyclin D1 and phosphorylated ribosomal S6 proteins in hemimegalencephaly. Acta Neuropathol, 2007, 114(4):287-293.
13. Miyata H, Chiang AC, Vinters HV. Insulin signaling pathways in cortical dysplasia and TSC-tubers:tissue microarray analysis. Ann Neurol, 2004, 56(10):510-519.
14. Baybis M, Yu J, Lee A, et al. mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann Neurol, 2004, 56(5):478-487.
15. Sha LZ, Xing XL, Zhang D, et al. Mapping the spatio-temporal pattern of the mammalian target of rapamycin (mTOR) activation in temporal lobe epilepsy. PLoS ONE, 2012, 7(1):e39152.
16. Sosunov AA, Wu X, McGovern RA, et al. The mTOR pathway is activated in glial cells in mesial temporal sclerosis. Epilepsia, 2012, 53(Suppl. 1):78-86.
17. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell, 2006, 22(9):159-168.
18. Backman SA, Stambolic V, Suzuki A, et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet, 2001, 29(7):396-403.
19. Kwon CH, Zhu X, Zhang J, et al. Pten regulates neuronal soma size:a mouse model of Lhermitte-Duclos disease. Nat Genet, 2001, 29(6):404-411.
20. Ljungberg MC, Sunnen CN, Lugo JN, et al. Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech, 2009, 2(5):389-398.
21. Sunnen CN, Brewster AL, Lugo JN, et al. Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice. Epilepsia, 2011, 52(8):2065-2075.
22. Brewster AL, Lugo JN, Patil VV, et al. Rapamycin reverses status epilepticus-induced memory deficits and dendritic damage. PLoS ONE, 2013, 8(2):e57808.
23. Hoeffer CA, Klann E. mTOR signaling:at the crossroads of plasticity, memory and disease. Trends Neurosci, 2010, 33(4):67-75.
24. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell, 2007, 12(10):9-22.
25. Talos DM, Sun H, Zhou X, et al. The interaction between early life epilepsy and autistic-like behavioral consequences:a role for the mammalian target of rapamycin (mTOR) pathway. PLoS ONE, 2012, 7(2):e35885.
26. Dello Russo C, Lisi L, Feinstein DL, et al. mTOR kinase, a key player in the regulation of glial functions:relevance for the therapy of multiple sclerosis. Glia, 2013, 61(7):301-311.
27. Vezzani A, French J, Bartfai T, et al. The role of inflammation in epilepsy. Nat Rev Neurol, 2011, 7(3):31-40.
28. Kettenmann H, Hanisch UK, Noda M, et al. Physiology of microglia. Physiol Rev, 2011, 91(7):461-553.
29. Bajorat R, Wilde M, Sellmann T, et al. Seizure frequency in pilocarpine-treated rats is independent of circadian rhythm. Epilepsia, 2011, 52(12):e118-e122.
30. Goffin K, Nissinen J, Van Laere K, et al. Cyclicity of spontaneous recurrent seizures in pilocarpine model of temporal lobe epilepsy in rat. Exp Neurol, 2007, 205(11):501-505.
31. Williams PA, White AM, Clark S, et al. Development of spontaneous recurrent seizures after kainate-induced status epilepticus. J Neurosci, 2009, 29(7):2103-2112.
32. Kadam SD, White AM, Staley KJ, et al. Continuous electroencephalographic monitoring with radio-telemetry in a rat model of perinatal hypoxia-ischemia reveals progressive post-stroke epilepsy. J Neurosci, 2010, 30(8):404-415.
33. Lasarge CL, Danzer SC. Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation. Front Mol Neurosci, 2014, 7(3):18.
34. Buckmaster PS, Ingram EA, Wen X. Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci, 2009, 29(7):8259-8269.
35. Ming GL, Song H. Adult neurogenesis in the mammalian brain:significant answers and significant questions. Neuron, 2011, 70(2):687-702.
36. Pun RY, Rolle IJ, Lasarge CL, et al. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron, 2012, 75:1022-1034.
37. Devinsky O, Vezzani A, Najjar S, et al. Glia and epilepsy:excitability and inflammation. Trends Neurosci, 2013, 36(7):174-184.
38. Krueger DA, Wilfong AA, Holland-Bouley K, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol, 2013, 74(5):679-687.
39. Zeng LH, Xu L, Gutmann DH, et al. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol, 2008, 63(2):444-453.
40. Zhou J, Blundell J, Ogawa S, et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci, 2009, 29(2):1773-1783.
41. Hailer NP. Immunosuppression after traumatic or ischemic CNS damage:it is neuroprotective and illuminates the role of microglial cells. Prog Neurobiol, 2008, 84(3):211-233.

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mTOR抑制剂抑制皮质发育不良小鼠癫痫发作

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