mTOR抑制劑抑制皮質發育不良小鼠癲癇發作_Journal of Epilepsy

Authors：

NguyenLH , BrewsterAL , ClarkME , Regnier-GolanovA , SunnenCN , PatilVV , D′ArcangeloG ,  AndersonAE , 遲瀟灑 , 慕潔

Corresponding?author：

AndersonAE, Email: annea@bcm.edu

Keywords：

皮質發育畸形; 癲癇; 雷帕霉素; 星形膠質細胞增生; 小膠質細胞增生

DOI：

10.7507/2096-0247.20170011

Video：

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哺乳動物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)在皮質發育不良(Cortical dysplasia, CD)及癲癇動物模型中超活化。在神經元特異性Pten基因敲除(Neuronsubset-specific Pten knockout, NS-Pten KO)小鼠模型中, 盡管在早期癲癇發生過程中抑制mTOR信號通路能夠減少癲癇樣活動, 但mTOR抑制劑在癲癇建立后的作用尚不清楚。文章通過建立伴有嚴重慢性癲癇的NS-Pten KO成年小鼠模型, 探究mTOR抑制劑對其癲癇樣活動和其他神經病理的作用。NS-Pten KO小鼠癲癇樣活動、mTOR信號通路的異常調節和相關神經病理隨年齡增長的變化通過視頻腦電(video-electroencephalography, VEEG), 蛋白免疫印跡和免疫組化檢測。NS-Pten KO小鼠出生后9周開始接受mTOR抑制劑雷帕霉素治療(10 mg/kg i.p, 5d/周)并采用VEEG監測癲癇樣活動。通過蛋白免疫印跡和免疫組化檢測雷帕霉素的作用。試驗發現, 隨著年齡增長, NS-Pten KO小鼠的癲癇樣活動惡化, 同時伴有mTOR復合物1和2(mTOR complex 1 and 2, mTORC1 and mTORC2)調節異常和進展性的星形膠質細胞和小膠質細胞增生。雷帕霉素治療抑制癲癇樣活動, 改善基線腦電活動并提高嚴重癲癇NS-PtenKO小鼠的預后。在分子水平, 雷帕霉素治療降低mTORC1和mTORC2水平并減少星形膠質細胞和小膠質細胞增生。研究表明在NS-Pten KO小鼠中, 雷帕霉素成功治療癲癇有較寬的時間窗。抑制mTOR可能是CD伴慢性癲癇及mTOR信號通路基因調節異常的潛在治療手段。

Citation： NguyenLH, BrewsterAL, ClarkME, Regnier-GolanovA, SunnenCN, PatilVV, D′ArcangeloG, AndersonAE, 遲瀟灑, 慕潔. mTOR抑制劑抑制皮質發育不良小鼠癲癇發作. Journal of Epilepsy, 2017, 3(1): 70-79. doi: 10.7507/2096-0247.20170011 Copy

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.

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抑制劑抑制皮質發育不良小鼠癲癇發作

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