Molecular Neurobiology

, Volume 46, Issue 3, pp 662–681 | Cite as

The mTOR Signaling Pathway in the Brain: Focus on Epilepsy and Epileptogenesis

  • Emilio Russo
  • Rita Citraro
  • Andrew Constanti
  • Giovambattista De Sarro
Article

Abstract

Recent evidence suggests that an altered mammalian (mechanistic) target of rapamycin (mTOR) signaling pathway and its pharmacological modulation might be implicated in several neurological diseases including epileptogenesis. mTOR is a molecular sensor, which regulates protein synthesis, enhancing mRNA translation of genes involved in the regulation of cell proliferation and survival, working as part of two distinct multimeric complexes known as mTORC1 and mTORC2. mTOR is an evolutionarily highly conserved serine/threonine kinase belonging to the phosphoinositide 3-kinase-related kinase family and represents one of the most recently studied pathways in relation to epilepsy and epileptogenesis, due to its suggested pivotal role in many aspects of cellular proliferation and growth also including neurodegeneration, neurogenesis, and synaptic plasticity. In this review, we report the cellular and molecular features of mTOR and related pathways, analyze their function in the brain including all current related evidence of their role, and finally, discuss the possible involvement of mTOR signaling in epileptogenesis and epilepsy, giving further consideration to future developments in this area.

Keywords

Rapamycin Antiepileptogenic Tuberous sclerosis complex (TSC) Seizure Temporal lobe epilepsy (TLE) Inflammation 

Notes

Acknowledgments

Funding needed to purchase articles for this survey were granted by the “Rete Regionale di informazione sul farmaco: informazione, formazione, e farmacovigilanza” Project Sponsored by Regione Calabria on the Behalf of Agenzia Italiana del Farmaco (AIFA).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Weichhart T (2012) Mammalian target of rapamycin: a signaling kinase for every aspect of cellular life. Methods Mol Biol 821:1–14PubMedCrossRefGoogle Scholar
  2. 2.
    Powell JD, Pollizzi KN, Heikamp EB, Horton MR (2012) Regulation of immune responses by mTOR. Annu Rev Immunol 30:39–68PubMedCrossRefGoogle Scholar
  3. 3.
    Sofroniadou S, Goldsmith D (2011) Mammalian target of rapamycin (mTOR) inhibitors: potential uses and a review of haematological adverse effects. Drug Saf 34:97–115PubMedCrossRefGoogle Scholar
  4. 4.
    Cho CH (2011) Frontier of epilepsy research—mTOR signaling pathway. Exp Mol Med 43:231–274PubMedCrossRefGoogle Scholar
  5. 5.
    Chong ZZ, Shang YC, Zhang L, Wang S, Maiese K (2010) Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. Oxid Med Cell Longev 3:374–391PubMedCrossRefGoogle Scholar
  6. 6.
    McDaniel SS, Wong M (2011) Therapeutic role of mammalian target of rapamycin (mTOR) inhibition in preventing epileptogenesis. Neurosci Lett 497:231–239PubMedCrossRefGoogle Scholar
  7. 7.
    Pitkänen A, Lukasiuk K (2011) Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol 10:173–186PubMedCrossRefGoogle Scholar
  8. 8.
    Pitkänen A, Lukasiuk K (2009) Molecular and cellular basis of epileptogenesis in symptomatic epilepsy. Epilepsy Behav 14:16–25PubMedCrossRefGoogle Scholar
  9. 9.
    Zara F, Bianchi A (2009) The impact of genetics on the classification of epilepsy syndromes. Epilepsia 50(Suppl 5):11–14PubMedCrossRefGoogle Scholar
  10. 10.
    Friedman A, Dingledine R (2011) Molecular cascades that mediate the influence of inflammation on epilepsy. Epilepsia 52:33–39PubMedCrossRefGoogle Scholar
  11. 11.
    Aronica E, Gorter JA (2007) Gene expression profile in temporal lobe epilepsy. Neuroscientist 13:100–108PubMedCrossRefGoogle Scholar
  12. 12.
    Wang YY, Smith P, Murphy M, Cook M (2010) Global expression profiling in epileptogenesis: does it add to the confusion? Brain Pathol 20:1–16PubMedCrossRefGoogle Scholar
  13. 13.
    Pitkänen A, Sutula TP (2002) Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol 1:173–181PubMedCrossRefGoogle Scholar
  14. 14.
    Temkin NR (2009) Preventing and treating posttraumatic seizures: the human experience. Epilepsia 2:S10–S13CrossRefGoogle Scholar
  15. 15.
    Jacobs MP, Leblanc GG, Brooks-Kayal A, Jensen FE, Lowenstein DH, Noebels JL, Spencer DD, Swann JW (2009) Curing epilepsy: progress and future directions. Epilepsy Behav 14:438–445PubMedCrossRefGoogle Scholar
  16. 16.
    Lasoń W, Dudra-Jastrzębska M, Rejdak K, Czuczwar SJ (2011) Basic mechanisms of antiepileptic drugs and their pharmacokinetic/pharmacodynamic interactions: an update. Pharmacol Rep 63:271–292PubMedGoogle Scholar
  17. 17.
    Mula M (2009) New antiepileptic drugs: molecular targets. Cent Nerv Syst Agents Med Chem 9:79–86PubMedCrossRefGoogle Scholar
  18. 18.
    Stafstrom CE (2010) Mechanisms of action of antiepileptic drugs: the search for synergy. Curr Opin Neurol 23:157–163PubMedCrossRefGoogle Scholar
  19. 19.
    Meldrum BS, Rogawski MA (2007) Molecular targets for antiepileptic drug development. Neurotherapeutics 4:18–61PubMedCrossRefGoogle Scholar
  20. 20.
    Reid CA, Jackson GD, Berkovic SF, Petrou S (2010) New therapeutic opportunities in epilepsy: a genetic perspective. Pharmacol Ther 128:274–280PubMedCrossRefGoogle Scholar
  21. 21.
    Garelick MG, Kennedy BK (2011) TOR on the brain. Exp Gerontol 46:155–163PubMedCrossRefGoogle Scholar
  22. 22.
    Bjedov I, Partridge L (2011) A longer and healthier life with TOR down-regulation: genetics and drugs. Biochem Soc Trans 39:460–465PubMedCrossRefGoogle Scholar
  23. 23.
    Rossi M, Caraglia M (2012) Molecular targets for the treatment of multiple myeloma. Current Cancer Drug Targets (in press)Google Scholar
  24. 24.
    Russell RC, Fang C, Guan KL (2011) An emerging role for TOR signaling in mammalian tissue and stem cell physiology. Development 138:3343–3356PubMedCrossRefGoogle Scholar
  25. 25.
    Zhang YJ, Duan Y, Zheng XF (2011) Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug Discov Today 16:325–331PubMedCrossRefGoogle Scholar
  26. 26.
    Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945PubMedCrossRefGoogle Scholar
  27. 27.
    Zhou H, Huang S (2010) The complexes of mammalian target of rapamycin. Curr Protein Pept Sci 11:409–424PubMedCrossRefGoogle Scholar
  28. 28.
    Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N (2010) Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta 1804:433–439PubMedCrossRefGoogle Scholar
  29. 29.
    Swiech L, Perycz M, Malik A, Jaworski J (2008) Role of mTOR in physiology and pathology of the nervous system. Biochim Biophys Acta 1784:116–132PubMedCrossRefGoogle Scholar
  30. 30.
    Hoeffer CA, Klann E (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 233:67–75CrossRefGoogle Scholar
  31. 31.
    Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, Oppliger W, Jenoe P, Hall MN (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10:457–468PubMedCrossRefGoogle Scholar
  32. 32.
    Proud CG (2011) A new link in the chain from amino acids to mTORC1 activation. Mol Cell 44:7–8PubMedCrossRefGoogle Scholar
  33. 33.
    Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM (2003) GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11:895–904PubMedCrossRefGoogle Scholar
  34. 34.
    Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137:873–886PubMedCrossRefGoogle Scholar
  35. 35.
    Wang L, Harris TE, Roth RA, Lawrence JC Jr (2007) PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 282:20036–20044PubMedCrossRefGoogle Scholar
  36. 36.
    Huang J, Wu S, Wu CL, Manning BD (2009) Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Res 69:6107–6114PubMedCrossRefGoogle Scholar
  37. 37.
    Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM (2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16:1865–1870PubMedCrossRefGoogle Scholar
  38. 38.
    Pearce LR, Huang X, Boudeau J, Pawłowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA, Alessi DR (2007) Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 405:513–522PubMedCrossRefGoogle Scholar
  39. 39.
    Pearce LR, Sommer EM, Sakamoto K, Wullschleger S, Alessi DR (2011) Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem J 436:169–179PubMedCrossRefGoogle Scholar
  40. 40.
    Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6:1122–1128PubMedCrossRefGoogle Scholar
  41. 41.
    Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159–168PubMedCrossRefGoogle Scholar
  42. 42.
    Bhagwat SV, Crew AP (2010) Novel inhibitors of mTORC1 and mTORC2. Curr Opin Investig Drugs 11:638–645PubMedGoogle Scholar
  43. 43.
    Dancey JE, Monzon J (2011) Ridaforolimus: a promising drug in the treatment of soft-tissue sarcoma and other malignancies. Future Oncol 7:827–839PubMedCrossRefGoogle Scholar
  44. 44.
    Khokhar NZ, Altman JK, Platanias LC (2011) Emerging roles for mammalian target of rapamycin inhibitors in the treatment of solid tumors and hematological malignancies. Curr Opin Oncol 23:578–586PubMedCrossRefGoogle Scholar
  45. 45.
    Marshall G, Howard Z, Dry J, Fenton S, Heathcote D, Gray N, Keen H, Logie A, Holt S, Smith P, Guichard SM (2011) Benefits of mTOR kinase targeting in oncology: pre-clinical evidence with AZD8055. Biochem Soc Trans 39:456–459PubMedCrossRefGoogle Scholar
  46. 46.
    Fingar DC, Blenis J (2004) Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23:3151–3171PubMedCrossRefGoogle Scholar
  47. 47.
    Huang S, Houghton PJ (2003) Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol 3:371–377PubMedCrossRefGoogle Scholar
  48. 48.
    Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, Ru B, Pan D (2002) Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 4:699–704PubMedCrossRefGoogle Scholar
  49. 49.
    Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657PubMedCrossRefGoogle Scholar
  50. 50.
    Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J (2002) Tuberous sclerosis complex-1 and −2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci U S A 99:13571–13576PubMedCrossRefGoogle Scholar
  51. 51.
    Zeng LH, Rensing NR, Zhang B, Gutmann DH, Gambello MJ, Wong M (2011) Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum Mol Genet 20:445–454PubMedCrossRefGoogle Scholar
  52. 52.
    Bai X, Ma D, Liu A, Shen X, Wang QJ, Liu Y, Jiang Y (2007) Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318:977–980PubMedCrossRefGoogle Scholar
  53. 53.
    Wang X, Fonseca BD, Tang H, Liu R, Elia A, Clemens MJ, Bommer UA, Proud CG (2008) Re-evaluating the roles of proposed modulators of mammalian target of Rapamycin complex 1 (mTORC1) signaling. J Biol Chem 283:30482–33092PubMedCrossRefGoogle Scholar
  54. 54.
    Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590PubMedCrossRefGoogle Scholar
  55. 55.
    Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100:328–341PubMedCrossRefGoogle Scholar
  56. 56.
    Hahn-Windgassen A, Nogueira V, Chen CC, Skeen JE, Sonenberg N, Hay N (2005) Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem 280:32081–32089PubMedCrossRefGoogle Scholar
  57. 57.
    Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893–2904PubMedCrossRefGoogle Scholar
  58. 58.
    Schneider A, Younis RH, Gutkind JS (2008) Hypoxia-induced energy stress inhibits the mTOR pathway by activating an AMPK/REDD1 signaling axis in head and neck squamous cell carcinoma. Neoplasia 10:1295–1302PubMedGoogle Scholar
  59. 59.
    Vadysirisack DD, Ellisen LW (2012) mTOR activity under hypoxia. Methods Mol Biol 821:45–58PubMedCrossRefGoogle Scholar
  60. 60.
    Kim MS, Kuehn HS, Metcalfe DD, Gilfillan AM (2008) Activation and function of the mTORC1 pathway in mast cells. J Immunol 180:4586–4595PubMedGoogle Scholar
  61. 61.
    Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:1496–1501PubMedCrossRefGoogle Scholar
  62. 62.
    Cully M, You H, Levine AJ, Mak TW (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6:184–192PubMedCrossRefGoogle Scholar
  63. 63.
    Ahn JY, Ye K (2005) PIKE GTPase signaling and function. Int J Biol Sci 1:44–50PubMedCrossRefGoogle Scholar
  64. 64.
    Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM (1998) RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci U S A 95:1432–1437PubMedCrossRefGoogle Scholar
  65. 65.
    Park IH, Bachmann R, Shirazi H, Chen J (2002) Regulation of ribosomal S6 kinase 2 by mammalian target of rapamycin. J Biol Chem 277:31423–31429PubMedCrossRefGoogle Scholar
  66. 66.
    Reinhard C, Thomas G, Kozma SC (1992) A single gene encodes two isoforms of the p70 S6 kinase: activation upon mitogenic stimulation. Proc Natl Acad Sci U S A 89:4052–4056PubMedCrossRefGoogle Scholar
  67. 67.
    Cole-Edwards KK, Bazan NG (2005) Lipid signaling in experimental epilepsy. Neurochem Res 30:847–853PubMedCrossRefGoogle Scholar
  68. 68.
    Levy DE, Lee CK (2002) What does Stat3 do? J Clin Invest 109:1143–1148PubMedGoogle Scholar
  69. 69.
    Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Cur Opin Cell Biol 17:596–603CrossRefGoogle Scholar
  70. 70.
    Yang Q, Inoki K, Kim E, Guan KL (2006) TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity. Proc Natl Acad Sci U S A 103:6811–6816PubMedCrossRefGoogle Scholar
  71. 71.
    Tanaka K, Babic I, Nathanson D, Akhavan D, Guo D, Gini B, Dang J, Zhu S, Yang H, de Jesus J, Amzajerdi AN, Zhang Y, Dibble CC, Dan H, Rinkenbaugh A, Yong WH, Vinters HV, Gera JF, Cavenee WK, Cloughesy TF, Manning BD, Baldwin AS, Mischel PS (2011) Oncogenic EGFR signaling activates an mTORC2–NF-κB pathway that promotes chemotherapy resistance. Cancer Discov 1:524–538PubMedCrossRefGoogle Scholar
  72. 72.
    Zinzalla V, Stracka D, Oppliger W, Hall MN (2011) Activation of mTORC2 by association with the ribosome. Cell 144:757–768PubMedCrossRefGoogle Scholar
  73. 73.
    Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274PubMedCrossRefGoogle Scholar
  74. 74.
    Aeder SE, Martin PM, Soh JW, Hussaini IM (2004) PKC-eta mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways. Oncogene 23:9062–9069PubMedCrossRefGoogle Scholar
  75. 75.
    Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11:859–871PubMedCrossRefGoogle Scholar
  76. 76.
    Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296–1302PubMedCrossRefGoogle Scholar
  77. 77.
    Lang F, Böhmer C, Palmada M, Seebohm G, Strutz-Seebohm N, Vallon V (2006) (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol Rev 86:1151–1178PubMedCrossRefGoogle Scholar
  78. 78.
    García-Martínez JM, Alessi DR (2008) mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 416:375–385PubMedCrossRefGoogle Scholar
  79. 79.
    Jones KT, Greer ER, Pearce D, Ashrafi K (2009) Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLos Biol 7:e60PubMedCrossRefGoogle Scholar
  80. 80.
    Proud CG (2007) Amino acids and mTOR signalling in anabolic function. Biochem Soc Trans 35:1187–1190PubMedCrossRefGoogle Scholar
  81. 81.
    Holz MK, Ballif BA, Gygi SP, Blenis J (2005) mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123:569–580PubMedCrossRefGoogle Scholar
  82. 82.
    Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG (2001) Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J 20:4370–4379PubMedCrossRefGoogle Scholar
  83. 83.
    Meijer AJ, Codogno P (2006) Signalling and autophagy regulation in health, aging and disease. Mol Aspects Med 27:411–425PubMedCrossRefGoogle Scholar
  84. 84.
    Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6:304–312PubMedCrossRefGoogle Scholar
  85. 85.
    Nyfeler B, Bergman P, Wilson CJ, Murphy LO (2012) Quantitative visualization of autophagy induction by mTOR inhibitors. Methods Mol Biol 821:239–250PubMedCrossRefGoogle Scholar
  86. 86.
    Cammalleri M, Lütjens R, Berton F, King AR, Simpson C, Francesconi W, Sanna PP (2003) Time-restricted role for dendritic activation of the mTOR–p70S6K pathway in the induction of late-phase long-term potentiation in the CA1. Proc Natl Acad Sci U S A 100:14368–14373PubMedCrossRefGoogle Scholar
  87. 87.
    Jaworski J, Spangler S, Seeburg DP, Hoogenraad CC, Sheng M (2005) Control of dendritic arborization by the phosphoinositide-3-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci 25:11300–11312PubMedCrossRefGoogle Scholar
  88. 88.
    Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ (2006) Hypothalamic mTOR signaling regulates food intake. Science 312:927–930PubMedCrossRefGoogle Scholar
  89. 89.
    Kumar V, Zhang MX, Swank MW, Kunz J, Wu GY (2005) Regulation of dendritic morphogenesis by Ras–PI3K–Akt–mTOR and Ras–MAPK signaling pathways. J Neurosci 25:11288–11299PubMedCrossRefGoogle Scholar
  90. 90.
    Miller FD, Kaplan DR (2003) Signaling mechanisms underlying dendrite formation. Curr Opin Neurobiol 13:391–398PubMedCrossRefGoogle Scholar
  91. 91.
    Bramham CR, Wells DG (2007) Dendritic mRNA: transport, translation and function. Nat Rev Neurosci 8:776–789PubMedCrossRefGoogle Scholar
  92. 92.
    Raab-Graham KF, Haddick PCG, Jan YN, Jan LY (2006) Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites. Science 314:144–148PubMedCrossRefGoogle Scholar
  93. 93.
    Tang SJ, Reis G, Kang H, Gingras AC, Sonenberg N, Schuman EM (2002) A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc Natl Acad Sci U S A 99:467–472PubMedCrossRefGoogle Scholar
  94. 94.
    Slipczuk L, Bekinschtein P, Katche C, Cammarota M, Izquierdo I, Medina JH (2009) BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS One 4:e6007PubMedCrossRefGoogle Scholar
  95. 95.
    Gobert D, Topolnik L, Azzi M, Huang L, Badeaux F, Desgroseillers L, Sossin WS, Lacaille JC (2008) Forskolin induction of late-LTP and up-regulation of 5′ TOP mRNAs translation via mTOR, ERK, and PI3K in hippocampal pyramidal cells. J Neurochem 106:1160–1174PubMedCrossRefGoogle Scholar
  96. 96.
    Kelleher RJ 3rd, Govindarajan A, Tonegawa S (2004) Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44:59–73PubMedCrossRefGoogle Scholar
  97. 97.
    Tsokas P, Grace EA, Chan P, Ma T, Sealfon SC, Iyengar R, Landau EM, Blitzer RD (2005) Local protein synthesis mediates a rapid increase in dendritic elongation factor 1A after induction of late long-term potentiation. J Neurosci 25:5833–5843PubMedCrossRefGoogle Scholar
  98. 98.
    Tsokas P, Ma T, Iyengar R, Landau EM, Blitzer RD (2007) Mitogen-activated protein kinase upregulates the dendritic translation machinery in long-term potentiation by controlling the mammalian target of rapamycin pathway. J Neurosci 27:5885–5894PubMedCrossRefGoogle Scholar
  99. 99.
    Jaworski J, Sheng M (2006) The growing role of mTOR in neuronal development and plasticity. Mol Neurobiol 34:205–219PubMedCrossRefGoogle Scholar
  100. 100.
    Schratt GM, Nigh EA, Chen WG, Hu L, Greenberg ME (2004) BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci 24:7366–7377PubMedCrossRefGoogle Scholar
  101. 101.
    Gong R, Park CS, Abbassi NR, Tang SJ (2006) Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons. J Biol Chem 281:18802–18815PubMedCrossRefGoogle Scholar
  102. 102.
    Kelly MT, Crary JF, Sacktor TC (2007) Regulation of protein kinase Mzeta synthesis by multiple kinases in long-term potentiation. J Neuroscience 27:3439–3444CrossRefGoogle Scholar
  103. 103.
    Lee CC, Huang CC, Wu MY, Hsu KS (2005) Insulin stimulates postsynaptic density-95 protein translation via the phosphoinositide 3-kinase–Akt–mammalian target of rapamycin signaling pathway. J Biol Chem 280:18543–18550PubMedCrossRefGoogle Scholar
  104. 104.
    Abel T, Lattal KM (2001) Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr Opin Neurobiol 11:180–187PubMedCrossRefGoogle Scholar
  105. 105.
    Dash PK, Orsi SA, Moore AN (2006) Spatial memory formation and memory enhancing effect of glucose involves activation of the tuberous sclerosis complex mammalian target of rapamycin pathway. J Neurosci 26:8048–8056PubMedCrossRefGoogle Scholar
  106. 106.
    Hoeffer CA, Tang W, Wong H, Santillan A, Patterson RJ, Martinez LA, Tejada-Simon MV, Paylor R, Hamilton SL, Klann E (2008) Removal of FKBP12 enhances mTOR–RAPTOR interactions, LTP, memory, and perseverative/repetitive behavior. Neuron 60:832–845PubMedCrossRefGoogle Scholar
  107. 107.
    Parsons RG, Gafford GM, Helmstetter FJ (2006) Translational control via the mammalian target of rapamycin pathway is critical for the formation and stability of long-term fear memory in amygdala neurons. J Neurosci 26:12977–12983PubMedCrossRefGoogle Scholar
  108. 108.
    Schicknick H, Schott BH, Budinger E, Smalla KH, Riedel A, Seidenbecher CI, Scheich H, Gundelfinger ED, Tischmeyer W (2008) Dopaminergic modulation of auditory cortex-dependent memory consolidation through mTOR. Cereb Cortex 18:2646–2658PubMedCrossRefGoogle Scholar
  109. 109.
    Tischmeyer W, Schicknick H, Kraus M, Seidenbecher CI, Staak S, Scheich H, Gundelfinger ED (2003) Rapamycin-sensitive signalling in long-term consolidation of auditory cortex-dependent memory. Eur J Neurosci 18:942–950PubMedCrossRefGoogle Scholar
  110. 110.
    Belelovsky K, Kaphzan H, Elkobi A, Rosenblum K (2009) Biphasic activation of the mTOR pathway in the gustatory cortex is correlated with and necessary for taste learning. J Neurosci 29:7424–7431PubMedCrossRefGoogle Scholar
  111. 111.
    Sui L, Wang J, Li BM (2008) Role of the phosphoinositide 3-kinase–Akt–mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex. Learn Mem 15:762–776PubMedCrossRefGoogle Scholar
  112. 112.
    Ehninger D, de Vries PJ, Silva AJ (2009) From mTOR to cognition: molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis. J Intellect Disabil Res 53:838–851PubMedCrossRefGoogle Scholar
  113. 113.
    Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, Ramesh V, Silva AJ (2008) Reversal of learning deficits in a Tsc2+/S mouse model of tuberous sclerosis. Nat Med 14:843–848PubMedCrossRefGoogle Scholar
  114. 114.
    Puighermanal E, Marsicano G, Busquets-Garcia A, Lutz B, Maldonado R, Ozaita A (2009) Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nat Neurosci 12:1152–1158PubMedCrossRefGoogle Scholar
  115. 115.
    Blouet C, Ono H, Schwartz GJ (2008) Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metab 8:459–467PubMedCrossRefGoogle Scholar
  116. 116.
    Mori H, Inoki K, Opland D, Muenzberg H, Villanueva EC, Faouzi M, Ikenoue T, Kwiatkowski D, Macdougald OA, Myers MG Jr, Guan KL (2009) Critical roles for theTSC-mTOR pathway in {beta}-cell function. Am J Physiol Endocrinol Metab 2297:1013–1022CrossRefGoogle Scholar
  117. 117.
    Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–205PubMedCrossRefGoogle Scholar
  118. 118.
    Roa J, Garcia-Galiano D, Varela L, Sánchez-Garrido MA, Pineda R, Castellano JM, Ruiz-Pino F, Romero M, Aguilar E, López M, Gaytan F, Diéguez C, Pinilla L, Tena-Sempere M (2009) The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology 150:5016–5026PubMedCrossRefGoogle Scholar
  119. 119.
    Cao R, Obrietan K (2010) mTOR signaling and entrainment of the mammalian circadian clock. Mol Cell Pharmacol 2:125–130PubMedGoogle Scholar
  120. 120.
    Inoki K, Corradetti MN, Guan KL (2005) Dysregulation of the TSC–mTOR pathway in human disease. Nat Genet 37:19–24PubMedCrossRefGoogle Scholar
  121. 121.
    Tsang CK, Qi H, Liu LF, Zheng XF (2007) Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today 12:112–124PubMedCrossRefGoogle Scholar
  122. 122.
    Ehninger D, Silva AJ (2011) Rapamycin for treating tuberous sclerosis and Autism Spectrum disorders. Trends Mol Med 17:78–87PubMedCrossRefGoogle Scholar
  123. 123.
    Pitkanen A (2010) Therapeutic approaches to epileptogenesis—hope on the horizon. Epilepsia 51:2–17PubMedCrossRefGoogle Scholar
  124. 124.
    Ljungberg MC, Sunnen CN, Lugo JN, Anderson AE, D’Arcangelo G (2009) Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech 2:389–398PubMedCrossRefGoogle Scholar
  125. 125.
    Krab LC, Goorden SM, Elgersma Y (2008) Oncogenes on my mind: ERK and MTOR signaling in cognitive diseases. Trends in Genetics: TIG 24:498–510PubMedCrossRefGoogle Scholar
  126. 126.
    Gorman PM, Kim S, Guo M, Melnyk RA, McLaurin J, Fraser PE, Bowie JU, Chakrabartty A (2008) Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer's disease mutants. BMC Neurosci 30:9–17Google Scholar
  127. 127.
    Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat Med 10:S2–S9PubMedCrossRefGoogle Scholar
  128. 128.
    Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O’Kane CJ, Rubinsztein DC (2004) Inhibition of Mtor induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595PubMedCrossRefGoogle Scholar
  129. 129.
    Berger Z, Ravikumar B, Menzies FM, Oroz LG, Underwood BR, Pangalos MN, Schmitt I, Wullner U, Evert BO, O'Kane CJ, Rubinsztein DC (2006) Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet 15:433–442PubMedCrossRefGoogle Scholar
  130. 130.
    An WL, Cowburn RF, Li L, Braak H, Alafuzoff I, Iqbal K, Winblad B, Pei JJ (2003) Upregulation of phosphorylated/activated p70S6 kinase and its relationship to neurofibrillary pathology in Alzheimer’s disease. Am J Pathol 163:591–607PubMedCrossRefGoogle Scholar
  131. 131.
    Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ (2005) Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. FEBS J 272:4211–4220PubMedCrossRefGoogle Scholar
  132. 132.
    Paccalin M, Pain-Barc S, Pluchon C, Paul C, Besson MN, Carret-Rebillat AS, Rioux-Bilan A, Gil R, Hugon J (2006) Activated mTOR and PKR kinases in lymphocytes correlate with memory and cognitive decline in Alzheimer's disease. Dement Geriatr Cogn Disord 22:320–326PubMedCrossRefGoogle Scholar
  133. 133.
    Pei JJ, Hugon J (2008) mTOR-dependent signalling in Alzheimer's disease. J Cell Mol Med 12:2525–2532PubMedCrossRefGoogle Scholar
  134. 134.
    Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One 5:9979CrossRefGoogle Scholar
  135. 135.
    Khurana V, Lu Y, Steinhilb ML, Oldham S, Shulman JM, Feany MB (2006) TOR mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr Biol 16:230–241PubMedCrossRefGoogle Scholar
  136. 136.
    Corradetti MN, Inoki K, Guan KL (2005) The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J Biol Chem 280:9769–9772PubMedCrossRefGoogle Scholar
  137. 137.
    Malagelada C, Ryu EJ, Biswas SC, Jackson-Lewis V, Greene LA (2006) RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson’s disease by amechanism involving mammalian target of rapamycin inactivation. J Neurosci 26:9996–10005PubMedCrossRefGoogle Scholar
  138. 138.
    Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA (2010) Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease. J Neurosci 30:1166–1175PubMedCrossRefGoogle Scholar
  139. 139.
    Santini E, Alcacer C, Cacciatore S, Heiman M, Hervé D, Greengard P, Girault JA, Valjent E, Fisone G (2009) L-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice. J Neurochem 108:621–633PubMedCrossRefGoogle Scholar
  140. 140.
    Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ (1995) Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 270:2320–2326PubMedCrossRefGoogle Scholar
  141. 141.
    Jung CH, Ro SH, Cao J, Otto NM, Kim DH (2010) mTOR regulation of autophagy. FEBS Lett 584:1287–1295PubMedCrossRefGoogle Scholar
  142. 142.
    Kalkman HO (2006) The role of the phosphatidylinositide 3-kinase-protein kinase B pathway in schizophrenia. Pharmacol Ther 110:117–134PubMedCrossRefGoogle Scholar
  143. 143.
    Karolewicz B, Cetin M, Aricioglu F (2011) Beyond the glutamate N-methyl D-aspartate receptor in major depressive disorder: the mTOR signaling pathway. Bull Clin Psychopharmacol 21:1–6CrossRefGoogle Scholar
  144. 144.
    Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran A, Stockmeier CA, Karolewicz B (2011) The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 35:1774–1779PubMedCrossRefGoogle Scholar
  145. 145.
    Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964PubMedCrossRefGoogle Scholar
  146. 146.
    Chan S, Scheulen ME, Johnston S, Mross K, Cardoso F, Dittrich C, Eiermann W, Hess D, Morant R, Semiglazov V, Borner M, Salzberg M, Ostapenko V, Illiger HJ, Behringer D, Bardy-Bouxin N, Boni J, Kong S, Cincotta M, Moore L (2005) Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23:5314–5322PubMedCrossRefGoogle Scholar
  147. 147.
    Martínez-Sanchis S, Bernal MC, Montagud JV, Candela G, Crespo J, Sancho A, Pallardó LM (2011) Effects of immunosuppressive drugs on the cognitive functioning of renal transplant recipients: a pilot study. J Clin Exp Neuropsychol 33:1016–1024PubMedCrossRefGoogle Scholar
  148. 148.
    Soefje SA, Karnad A, Brenner AJ (2011) Common toxicities of mammalian target of rapamycin inhibitors. Target Oncol 6:125–129PubMedCrossRefGoogle Scholar
  149. 149.
    van de Beek D, Kremers WK, Kushwaha SS, McGregor CG, Wijdicks EF (2009) No major neurologic complications with sirolimus use in heart transplant recipients. Mayo Clin Proc 84:330–332PubMedGoogle Scholar
  150. 150.
    Lang F, Görlach A, Vallon V (2009) Targeting SGK1 in diabetes. Expert Opin Ther Targets 13:1303–1311PubMedCrossRefGoogle Scholar
  151. 151.
    Hoppe C, Elger CE (2011) Depression in epilepsy: a critical review from a clinical perspective. Nat Rev Neurol 7:462–472PubMedCrossRefGoogle Scholar
  152. 152.
    Luoni C, Bisulli F, Canevini MP, De Sarro G, Fattore C, Galimberti CA, Gatti G, La Neve A, Muscas G, Specchio LM, Striano S, Perucca E, on behalf of the SOPHIE Study Group (2011) Determinants of health-related quality of life in pharmacoresistant epilepsy: results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments. Epilepsia 52:2181–2191PubMedCrossRefGoogle Scholar
  153. 153.
    Manni R, Terzaghi M (2010) Comorbidity between epilepsy and sleep disorders. Epilepsy Res 90:171–177PubMedCrossRefGoogle Scholar
  154. 154.
    Costa J, Fareleira F, Ascenção R, Borges M, Sampaio C, Vaz-Carneiro A (2011) Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: a systematic review and meta-analysis. Epilepsia 52:1280–1291PubMedCrossRefGoogle Scholar
  155. 155.
    Okamoto OK, Janjoppi L, Bonone FM, Pansani AP, da Silva AV, Scorza FA, Cavalheiro EA (2010) Whole transcriptome analysis of the hippocampus: toward a molecular portrait of epileptogenesis. BMC Genomics 11:230PubMedCrossRefGoogle Scholar
  156. 156.
    Poduri A, Lowenstein D (2011) Epilepsy genetics—past, present, and future. Curr Opin Genet Dev 21:325–332PubMedCrossRefGoogle Scholar
  157. 157.
    Cheadle JP, Reeve MP, Sampson JR, Kwiatkowski DJ (2000) Molecular genetic advances in tuberous sclerosis. Hum Genet 107:97–114PubMedCrossRefGoogle Scholar
  158. 158.
    Onda H, Crino PB, Zhang H, Murphey RD, Rastelli L, Gould Rothberg BE, Kwiatkowski DJ (2002) Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway. Mol Cell Neurosci 21:561–574PubMedCrossRefGoogle Scholar
  159. 159.
    Crino PB, Nathanson KL, Henske EP (2006) The tuberous sclerosis complex. N Engl J Med 355:1345–1356PubMedCrossRefGoogle Scholar
  160. 160.
    Franz DN (2007) mTOR in tuberous sclerosis and other neurological disorders. Epilepsia 48:1630–1631PubMedCrossRefGoogle Scholar
  161. 161.
    Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, Kwiatkowski DJ (2008) Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci 28:5422–5432PubMedCrossRefGoogle Scholar
  162. 162.
    Zeng LH, Xu L, Gutmann DH, Wong M (2008) Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 63:444–453PubMedCrossRefGoogle Scholar
  163. 163.
    Waltereit R, Welzl H, Dichgans J, Lipp HP, Schmidt WJ, Weller M (2006) Enhanced episodic-like memory and kindling epilepsy in a rat model of tuberous sclerosis. J Neurochem 96:407–413PubMedCrossRefGoogle Scholar
  164. 164.
    Wenzel HJ, Patel LS, Robbins CA, Emmi A, Yeung RS, Schwartzkroin PA (2004) Morphology of cerebral lesions in the Eker rat model of tuberous sclerosis. Acta Neuropathol 108:97–108PubMedCrossRefGoogle Scholar
  165. 165.
    Goto J, Talos DM, Klein P, Qin W, Chekaluk YI, Anderl S, Malinowska IA, Di Nardo A, Bronson RT, Chan JA, Vinters HV, Kernie SG, Jensen FE, Sahin M, Kwiatkowski DJ (2011) Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proc Natl Acad Sci U S A 108:1070–1079CrossRefGoogle Scholar
  166. 166.
    Anderl S, Freeland M, Kwiatkowski DJ, Goto J (2011) Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex. Hum Mol Genet 20:4597–4604PubMedCrossRefGoogle Scholar
  167. 167.
    Wong M, Ess KC, Uhlmann EJ, Jansen LA, Li W, Crino PB, Mennerick S, Yamada KA, Gutmann DH (2003) Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Ann Neurol 54:251–256PubMedCrossRefGoogle Scholar
  168. 168.
    Zeng LH, McDaniel SS, Rensing N, Wong M (2010) Regulation of cell death and epileptogenesis by the mammalian target of rapamycin (mTOR): a double-edged sword? Cell Cycle 9:2281–2285PubMedCrossRefGoogle Scholar
  169. 169.
    Fu C, Cawthon B, Clinkscales W, Bruce A, Winzenburger P, Ess KC (2012) GABAergic interneuron development and function is modulated by the Tsc1 gene. Cereb Cortex (in press)Google Scholar
  170. 170.
    Buckmaster PS, Wen X (2011) Rapamycin suppresses axon sprouting by somatostatin interneurons in a mouse model of temporal lobe epilepsy. Epilepsia 52:2057–2064PubMedCrossRefGoogle Scholar
  171. 171.
    Buckmaster PS, Lew FH (2011) Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. J Neurosci 31:2337–2347PubMedCrossRefGoogle Scholar
  172. 172.
    Buckmaster PS, Ingram EA, Wen X (2009) 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 29:8259–8269PubMedCrossRefGoogle Scholar
  173. 173.
    Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, Cao Z, Gruenthal M, Huang Y (2010) Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis 40:193–199PubMedCrossRefGoogle Scholar
  174. 174.
    Sunnen CN, Brewster AL, Lugo JN, Vanegas F, Turcios E, Mukhi S, Parghi D, D'Arcangelo G, Anderson AE (2011) Inhibition of the mammalian target of Rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice. Epilepsia 52:2065–2075PubMedCrossRefGoogle Scholar
  175. 175.
    Zeng LH, Rensing NR, Wong M (2009) The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neuroscience 29:6964–6972CrossRefGoogle Scholar
  176. 176.
    Asnaghi L, Calastretti A, Bevilacqua A, D’Agnano I, Gatti G, Canti G, Delia D, Capaccioli S, Nicolin A (2004) Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene 23:5781–5791PubMedCrossRefGoogle Scholar
  177. 177.
    Castedo M, Ferri KF, Kroemer G (2002) Mammalian target of rapamycin (mTOR): pro- and anti-apoptotic. Cell Death Differ 9:99–100PubMedCrossRefGoogle Scholar
  178. 178.
    Sliwa A, Plucinska G, Bednarczyk J, Lukasiuk K (2012) Post-treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy. Neurosci Lett 509(2):105–109PubMedCrossRefGoogle Scholar
  179. 179.
    Zhang B, Wong M (2012) Pentylenetetrazole-induced seizures cause acute, but not chronic, mTOR pathway activation in rat. Epilepsia 53(3):506–511PubMedCrossRefGoogle Scholar
  180. 180.
    Baybis M, Yu J, Lee A, Golden JA, Weiner H, McKhann G 2nd, Aronica E, Crino PB (2004) mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann Neurol 56:478–487PubMedCrossRefGoogle Scholar
  181. 181.
    Wong (2011) Rapamycin for treatment of epilepsy: antiseizure, antiepileptogenic, both, or neither? Epilepsy Curr 11:66–68PubMedCrossRefGoogle Scholar
  182. 182.
    Ljungberg MC, Bhattacharjee MB, Lu Y, Armstrong DL, Yoshor D, Swann JW, Sheldon M, D'Arcangelo G (2006) Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol 60:420–429PubMedCrossRefGoogle Scholar
  183. 183.
    Wolf HK, Wiestler OD (1999) Malformative and neoplastic glioneuronal lesions in patients with chronic pharmacoresistant epilepsies. Adv Neurol 81:69–79PubMedGoogle Scholar
  184. 184.
    Boer K, Troost D, Timmermans W, van Rijen PC, Spliet WG, Aronica E (2010) Pi3K–mTOR signaling and AMOG expression in epilepsy-associated glioneuronal tumors. Brain Pathol 20:234–244PubMedCrossRefGoogle Scholar
  185. 185.
    Krueger DA, Care MM, Holland K, Agricola K, Tydor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363:1801–1811PubMedCrossRefGoogle Scholar
  186. 186.
    McDaniel SS, Rensing NR, Thio LL, Yamada KA, Wong M (2011) The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia 52:7–11CrossRefGoogle Scholar
  187. 187.
    Ruegg S, Baybis M, Juul H, Dichter M, Crino PB (2007) Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons. Epilepsy Res 77:85–92PubMedCrossRefGoogle Scholar
  188. 188.
    Wang Y, Barbaro MF, Baraban SC (2006) A role for the mTOR pathway in surface expression of AMPA receptors. Neurosci Lett 401:35–39PubMedCrossRefGoogle Scholar
  189. 189.
    Shacka JJ, Lu J, Xie ZL, Uchiyama Y, Roth KA, Zhang J (2007) Kainic acid induces early and transient autophagic stress in mouse hippocampus. Neurosci Lett 414:57–60PubMedCrossRefGoogle Scholar
  190. 190.
    Cao L, Xu J, Lin Y, Zhao X, Liu X, Chi Z (2009) Autophagy is upregulated in rats with status epilepticus and partly inhibited by vitamin E. Biochem Biophys Res Commun 379:949–953PubMedCrossRefGoogle Scholar
  191. 191.
    Vezzani A, French J, Bartfai T, Baram TZ (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7:31–40PubMedCrossRefGoogle Scholar
  192. 192.
    Aronica E, Crino PB (2011) Inflammation in epilepsy: clinical observations. Epilepsia 52:26–32PubMedCrossRefGoogle Scholar
  193. 193.
    Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG (2006) Rapamycin promotes expansion of functional CD4 + CD25 + FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 177:8338–83347PubMedGoogle Scholar
  194. 194.
    Gomez-Cambronero J (2003) Rapamycin inhibits GM-CSF-induced neutrophil migration. FEBS Lett 550:94–100PubMedCrossRefGoogle Scholar
  195. 195.
    Weichhart T, Säemann MD (2009) The multiple facets of mTOR in immunity. Trends Immunol 30:218–226PubMedCrossRefGoogle Scholar
  196. 196.
    Dello Russo C, Lisi L, Tringali G, Navarra P (2009) Involvement of mTOR kinase in cytokine-dependent microglial activation and cell proliferation. Biochem Pharmacol 78:1242–1251PubMedCrossRefGoogle Scholar
  197. 197.
    Weichhart T, Costantino G, Poglitsch M, Rosner M, Zeyda M, Stuhlmeier KM, Kolbe T, Stulnig TM, Hörl WH, Hengstschläger M, Müller M, Säemann MD (2008) The TSC–mTOR signaling pathway regulates the innate inflammatory response. Immunity 29:565–577PubMedCrossRefGoogle Scholar
  198. 198.
    Hardie DG (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 25:1895–1908PubMedCrossRefGoogle Scholar
  199. 199.
    Kang CB, Hong Y, Dhe-Paganon S, Yoon HS (2008) FKBP family proteins: immunophilins with versatile biological functions. Neurosignals 16:318–325PubMedCrossRefGoogle Scholar
  200. 200.
    Edlich F, Lücke C (2011) From cell death to viral replication: the diverse functions of the membrane-associated FKBP38. Curr Opin Pharmacol 11:348–353PubMedCrossRefGoogle Scholar
  201. 201.
    Wouters BG, Koritzinsky M (2008) Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 8:851–864PubMedCrossRefGoogle Scholar
  202. 202.
    Haeusler RA, Accili D (2008) The double life of Irs. Cell Metab 8:7–9PubMedCrossRefGoogle Scholar
  203. 203.
    White MF (2003) Insulin signaling in health and disease. Science 302:1710–1711PubMedCrossRefGoogle Scholar
  204. 204.
    Raimondi C, Falasca M (2011) Targeting PDK1 in cancer. Curr Med Chem 18:2763–2769PubMedCrossRefGoogle Scholar
  205. 205.
    Ciraolo E, Morello F, Hirsch E (2011) Present and future of PI3K pathway inhibition in cancer: perspectives and limitations. Curr Med Chem 18:2674–2685PubMedCrossRefGoogle Scholar
  206. 206.
    Vazquez F, Devreotes P (2006) Regulation of PTEN function as a PIP3 gatekeeper through membrane interaction. Cell Cycle 5:1523–1527PubMedCrossRefGoogle Scholar
  207. 207.
    Hollander MC, Blumenthal GM, Dennis PA (2011) PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 11:289–301PubMedCrossRefGoogle Scholar
  208. 208.
    DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW (2008) Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 22:239–251PubMedCrossRefGoogle Scholar
  209. 209.
    Avruch J, Hara K, Lin Y, Liu M, Long X, Ortiz-Vega S, Yonezawa K (2006) Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene 25:6361–6372PubMedCrossRefGoogle Scholar
  210. 210.
    Avruch J, Long X, Lin Y, Ortiz-Vega S, Rapley J, Papageorgiou A, Oshiro N, Kikkawa U (2009) Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor. Biochem Soc Trans 37:223–226PubMedCrossRefGoogle Scholar
  211. 211.
    Han JM, Sahin M (2011) TSC1/TSC2 signaling in the CNS. FEBS Lett 585:973–980PubMedCrossRefGoogle Scholar
  212. 212.
    Jiang X, Yeung RS (2006) Regulation of microtubule-dependent protein transport by the TSC2/mammalian target of rapamycin pathway. Cancer Res 66:5258–5269PubMedCrossRefGoogle Scholar
  213. 213.
    Kaul G, Pattan G, Rafeequi T (2011) Eukaryotic elongation factor-2 (eEF2): its regulation and peptide chain elongation. Cell Biochem Funct 29:227–234PubMedCrossRefGoogle Scholar
  214. 214.
    Origanti S, Nowotarski SL, Carr TD, Sass-Kuhn S, Xiao L, Wang JY, Shantz LM (2012) Ornithine decarboxylase mRNA is stabilized in an mTORC1-dependent manner in Ras-transformed cells. Biochem J 442(1):199–207PubMedCrossRefGoogle Scholar
  215. 215.
    Moschella PC, Rao VU, McDermott PJ, Kuppuswamy D (2007) Regulation of mTOR and S6K1 activation by the nPKC isoforms, PKCepsilon and PKCdelta, in adult cardiac muscle cells. J Mol Cell Cardiol 43:754–766PubMedCrossRefGoogle Scholar
  216. 216.
    Stark DT, Bazan NG (2011) Neuroprotectin D1 induces neuronal survival and downregulation of amyloidogenic processing in Alzheimer's disease cellular models. Mol Neurobiol 43:131–138PubMedCrossRefGoogle Scholar
  217. 217.
    Zhan J, Easton JB, Huang S, Mishra A, Xiao L, Lacy ER, Kriwacki RW, Houghton PJ (2007) Negative regulation of ASK1 by p21Cip1 involves a small domain that includes Serine 98 that is phosphorylated by ASK1 in vivo. Mol Cell Biol 27:3530–3541PubMedCrossRefGoogle Scholar
  218. 218.
    Lee M, Theodoropoulou M, Graw J, Roncaroli F, Zatelli MC, Pellegata NS (2011) Levels of p27 sensitize to dual PI3K/mTOR inhibition. Mol Cancer Ther 10:1450–1459PubMedCrossRefGoogle Scholar
  219. 219.
    Usui I, Haruta T, Iwata M, Takano A, Uno T, Kawahara J, Ueno E, Sasaoka T, Kobayashi M (2000) Retinoblastoma protein phosphorylation via PI 3-kinase and mTOR pathway regulates adipocyte differentiation. Biochem Biophys Res Commun 275:115–120PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Emilio Russo
    • 1
  • Rita Citraro
    • 1
  • Andrew Constanti
    • 2
  • Giovambattista De Sarro
    • 1
  1. 1.Science of Health Department, School of MedicineUniversity “Magna Graecia” of CatanzaroCatanzaroItaly
  2. 2.Department of PharmacologyUCL School of PharmacyLondonUK

Personalised recommendations