Ribosomal protein S6 phosphorylation in the nervous system: From regulation to function

Frontiers in Molecular Neuroscience

Volumn 8, Issue DEC, 2015, Pages

  Biever, Anne ^a,b,c   Valjent, Emmanuel ^a,b,c   Puighermanal, Emma ^a,b,c  

^a INSTITUT DE GÉNOMIQUE FONCTIONNELLE   (France)

^b INSERM   (France)

^c UNIV MONTPELLIER   (France)

Author keywords

Brain; mRNA translation; mTOR; PP 1; Ribosome; RpS6 phosphorylation; S6K; Signaling cascades

Indexed keywords

6 CHLORO 2,3,4,5 TETRAHYDRO 7,8 DIHYDROXY 1 PHENYL 1H 3 BENZAZEPINE; AMPHETAMINE; APOMORPHINE; CERULENIN; CLOZAPINE; COCAINE; DIZOCILPINE; GHRELIN; HALOPERIDOL; INSULIN; KAINIC ACID; KETAMINE; LEPTIN; LEVODOPA; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE 1; MORPHINE; OLANZAPINE; PAPAVERINE; PENTETRAZOLE; PHENYLALANINE; PILOCARPINE; PROTEIN S6; QUINELORANE; QUINPIROLE; TETRAHYDROCANNABINOL;

ARTICLE; HUMAN; NERVE CELL PLASTICITY; NONHUMAN; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEOMICS; RNA TRANSLATION; SEQUENCE ANALYSIS; SIGNAL TRANSDUCTION; TUBEROUS SCLEROSIS;

EID: 84957810070     PISSN: 16625099     EISSN: None     Source Type: Journal    
DOI: 10.3389/fnmol.2015.00075     Document Type: Article

References (162)

1. Amendola, E., Zhan, Y., Mattucci, C., Castroflorio, E., Calcagno, E., Fuchs, C., et al. (2014). Mapping pathological phenotypes in a mouse model of CDKL5 disorder. PLoS ONE 9:e91613. doi: 10.1371/journal.pone.0091613
2. An, W. L., Cowburn, R. F., Li, L., Braak, H., Alafuzoff, I., Iqbal, K., et al. (2003). Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease. Am. J. Pathol. 163, 591-607. doi: 10.1016/S0002-9440(10)63687-5
3. Antion, M. D., Hou, L., Wong, H., Hoeffer, C. A., and Klann, E. (2008a). mGluR- dependent long-term depression is associated with increased phosphorylation of S6 and synthesis of elongation factor 1A but remains expressed in S6K- deficient mice. Mol. Cell. Biol. 28, 2996-3007. doi: 10.1128/MCB.00201-08
4. Antion, M. D., Merhav, M., Hoeffer, C. A., Reis, G., Kozma, S. C., Thomas, G., et al. (2008b). Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity. Learn. Mem. 15, 29-38. doi: 10.1101/lm.661908
5. Aronica, E., Boer, K., Baybis, M., Yu, J., and Crino, P. (2007). Co-expression of cyclin D1 and phosphorylated ribosomal S6 proteins in hemimegalencephaly. ActaNeuropathol. 114, 287-293. doi: 10.1007/s00401-007-0225-6
6. Bailey, J., Ma, D., and Szumlinski, K. K. (2012). Rapamycin attenuates the expression of cocaine-induced place preference and behavioral sensitization. Addict. Biol. 17, 248-258. doi: 10.1111/j.1369-1600.2010.00311.x
7. Bandi, H. R., Ferrari, S., Krieg, J., Meyer, H. E., and Thomas, G. (1993). Identification of 40 S ribosomal protein S6 phosphorylation sites in Swiss mouse 3T3 fibroblasts stimulated with serum. J. Biol. Chem. 268, 4530-4533.
8. Banerjee, S., Crouse, N. R., Emnett, R. J., Gianino, S. M., and Gutmann, D. H. (2011). Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner. Proc. Natl. Acad. Sci. U.S.A. 108, 15996-16001. doi: 10.1073/pnas.1019012108
9. Barak, S., Liu, F., Ben Hamida, S., Yowell, Q. V., Neasta, J., Kharazia, V., et al. (2013). Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse. Nat.Neurosci. 16,1111-1117. doi: 10.1038/nn.3439
10. Bateup, H. S., Takasaki, K. T., Saulnier, J. L., Denefrio, C. L., and Sabatini, B.L. (2011). Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J. Neurosci. 31, 8862-8869. doi: 10.1523/JNEUR0SCI.1617-11.2011
11. Baybis, M., Yu, J., Lee, A., Golden, J. A., Weiner, H., McKhann, G. II, et al. (2004). mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann. Neurol. 56,478-487. doi: 10.1002/ana.20211
12. Belandia, B., Brautigan, D., and Martin-Perez, J. (1994). Attenuation of ribosomal protein S6 phosphatase activity in chicken embryo fibroblasts transformed by Rous sarcoma virus. Mol. Cell. Biol. 14, 200-206. doi: 10.1128/MCB.14.1.200
13. Bernard, P. B., Castano, A. M., O'Leary, H., Simpson, K., Browning, M. D., and Benke, T. A. (2013). Phosphorylation of FMRP and alterations of FMRP complex underlie enhanced mLTD in adult rats triggered by early life seizures. Neurobiol. Dis. 59, 1-17. doi: 10.1016/j.nbd.2013.06.013
14. Bertran-Gonzalez, J., Chieng, B. C., Laurent, V., Valjent, E., and Balleine, B.W. (2012). Striatal cholinergic interneurons display activity-related phosphorylation of ribosomal protein S6. PLoS ONE 7:e53195. doi: 10.1371/journal.pone.0053195
15. Bhattacharya, A., Kaphzan, H., Alvarez-Dieppa, A. C., Murphy, J. P., Pierre, P., and Klann, E. (2012). Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 76, 325-337. doi: 10.1016/j.neuron.2012.07.022
16. Biever, A., Puighermanal, E., Nishi, A., David, A., Panciatici, C., Longueville, S., et al. (2015). PKA-dependent phosphorylation of ribosomal protein S6 does not correlate with translation efficiency in striatonigral and striatopallidal medium-sized spiny neurons. J. Neurosci. 35, 4113-4130. doi: 10.1523/JNEUROSCI.3288-14.2015
17. Bonito-Oliva, A., Pallottino, S., Bertran-Gonzalez, J., Girault, J. A., Valjent, E., and Fisone, G. (2013). Haloperidol promotes mT0RC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32kDa and inhibition of protein phosphatase-1. Neuropharmacology 72, 197-203. doi: 10.1016/j.neuropharm.2013.04.043
18. Bowling, H., Zhang, G., Bhattacharya, A., Perez-Cuesta, L. M., Deinhardt, K., Hoeffer, C. A., et al. (2014). Antipsychotics activate mT0RC1-dependent translation to enhance neuronal morphological complexity. Sci. Signal. 7:ra4. doi: 10.1126/scisignal.2004331
19. Brewster, A. L., Lugo, J. N., Patil, V. V., Lee, W. L., Qian, Y., Vanegas, F., et al. (2013). Rapamycin reverses status epilepticus-induced memory deficits and dendritic damage. PLoS ONE 8:e57808. doi: 10.1371/journal.pone.0057808
20. Burkhard, S. J., and Traugh, J. A. (1983). Changes in ribosome function by cAMP- dependent and cAMP-independent phosphorylation of ribosomal protein S6. J. Biol. Chem. 258, 14003-14008.
21. Caccamo, A., Branca, C., Talboom, J. S., Shaw, D. M., Turner, D., Ma, L., et al. (2015). Reducing ribosomal protein S6 kinase 1 expression improves spatial memory and synaptic plasticity in a mouse model of Alzheimer's disease. J. Neurosci. 35, 14042-14056. doi: 10.1523/JNEUROSCI.2781-15.2015
22. Cao, R., Anderson, F. E., Jung, Y. J., Dziema, H., and Obrietan, K. 2011. Circadian regulation of mammalian target of rapamycin signaling in the mouse suprachiasmatic nucleus. Neuroscience 181, 79-88. doi: 10.1016/j.neuroscience.2011.03.005
23. Chalhoub, N., Kozma, S. C., and Baker, S. J. (2006). S6k1 is not required for Pten-deficient neuronal hypertrophy. Brain Res. 1100, 32-41. doi: 10.1016/j.brainres.2006.05.013
24. Chan, J. A., Zhang, H., Roberts, P. S., Jozwiak, S., Wieslawa, G., Lewin-Kowalik, J., et al. (2004). Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J. Neuropathol. Exp. Neurol. 63, 1236-1242.
25. Chauvin, C., Koka, V., Nouschi, A., Mieulet, V., Hoareau-Aveilla, C., Dreazen, A., et al. (2014). Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program. Oncogene 33, 474-483. doi: 10.1038/onc.2012.606
26. Chen, L., Hu, L., Dong, J. Y., Ye, Q., Hua, N., Wong, M., et al. (2012). Rapamycin has paradoxical effects on S6 phosphorylation in rats with and without seizures. Epilepsia 53, 2026-2033. doi: 10.1111/epi.12013
27. Chen, S., Atkins, C. M., Liu, C. L., Alonso, O. F., Dietrich, W. D., and Hu, B. R. (2007). Alterations in mammalian target of rapamycin signaling pathways after traumatic brain injury. J. Cereb. Blood Flow Metab. 27, 939-949. doi: 10.1038/sj.jcbfm.9600393
28. Chevere-Torres, I., Kaphzan, H., Bhattacharya, A., Kang, A., Maki, J. M., Gambello, M. J., et al. (2012). Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the DeltaRG mouse model of tuberous sclerosis complex. Neurobiol. Dis. 45, 1101-1110. doi: 10.1016/j.nbd.2011.12.028
29. Cota, D., Matter, E. K., Woods, S. C., and Seeley, R. J. (2008). The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet- induced obesity. J. Neurosci. 28, 7202-7208. doi: 10.1523/JNEUROSCI.1389-08.2008
30. Cota, D., Proulx, K., Smith, K. A., Kozma, S. C., Thomas, G., Woods, S. C., et al. (2006). Hypothalamic mTOR signaling regulates food intake. Science 312, 927-930. doi: 10.1126/science.1124147
31. Culver, B. P., Savas, J. N., Park, S. K., Choi, J. H., Zheng, S., Zeitlin, S. O., et al. (2012). Proteomic analysis of wild-type and mutant huntingtin- associated proteins in mouse brains identifies unique interactions and involvement in protein synthesis. J. Biol. Chem. 287, 21599-21614. doi: 10.1074/jbc.M112.359307
32. Dennis, P. B., Pullen, N., Pearson, R. B., Kozma, S. C., and Thomas, G. (1998). Phosphorylation sites in the autoinhibitory domain participate in p70(s6k) activation loop phosphorylation. J. Biol. Chem. 273, 14845-14852. doi: 10.1074/jbc.273.24.14845
33. Domanskyi, A., Geissler, C., Vinnikov, I. A., Alter, H., Schober, A., Vogt, M. A., et al. (2011). Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson's disease models. FASEB J. 25, 2898-2910. doi: 10.1096/fj.11-181958
34. Duncan, R., and McConkey, E. H. (1982). Rapid alterations in initiation rate and recruitment of inactive RNA are temporally correlated with S6 phosphorylation. Eur. J. Biochem. 123, 539-544. doi: 10.1111/j.1432-1033.1982.tb06565.x
35. Dwyer, J. M., Maldonado-Aviles, J. G., Lepack, A. E., Dileone, R. J., and Duman, R. S. (2015). Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior. Proc. Natl. Acad. Sci. U.S.A. 112, 6188-6193. doi: 10.1073/pnas.1505289112
36. Easton, R. M., Cho, H., Roovers, K., Shineman, D. W., Mizrahi, M., Forman, M. S., et al. (2005). Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol. Cell. Biol. 25, 1869-1878. doi: 10.1128/MCB.25.5.1869-1878.2005
37. Ehninger, D., Han, S., Shilyansky, C., Zhou, Y., Li, W., Kwiatkowski, D. J., et al. (2007) Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat. Med. 14, 843-848. doi: 10.1038/nm1788
38. Feliciano, D. M., Su, T., Lopez, J., Platel, J. C., and Bordey, A. (2011). Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice. J. Clin.Invest. 121,1596-1607. doi: 10.1172/JCI44909
39. Ferrari, S., Bandi, H. R., Hofsteenge, J., Bussian, B. M., and Thomas, G. (1991). Mitogen-activated 70K S6 kinase. Identification of in vitro 40 S ribosomal S6 phosphorylation sites. J. Biol. Chem. 266, 22770-22775.
40. Fox, J. H., Connor, T., Chopra, V., Dorsey, K., Kama, J. A., Bleckmann, D., et al. (2010). The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease. Mol. Neurodegener. 5, 26. doi: 10.1186/1750-1326-5-26
41. Gangarossa, G., Ceolin, L., Paucard, A., Lerner-Natoli, M., Perroy, J., Fagni, L., et al. (2014). Repeated stimulation of dopamine D1-like receptor and hyperactivation of mTOR signaling lead to generalized seizures, altered dentate gyrus plasticity, and memory deficits. Hippocampus 24, 1466-1481. doi: 10.1002/hipo.22327
42. Gangarossa, G., Di Benedetto, M., O'Sullivan, G. J., Dunleavy, M., Alcacer, Bonito-Oliva, A., et al. (2011). Convulsant doses of a dopamine D1 receptor agonist result in Erk-dependent increases in Zif268 and Arc/Arg3.1 expression in mouse dentate gyrus. PLoS ONE 6:e19415. doi: 10.1371/journal.pone.0019415
43. Gangarossa, G., Perroy, J., and Valjent, E. (2013). Combinatorial topography and cell-type specific regulation of the ERK pathway by dopaminergic agonists in the mouse striatum. Brain Struct. Funct. 218, 405-419. doi: 10.1007/s00429-012-0405-6
44. Gangarossa, G., and Valjent, E. (2012). Regulation of the ERK pathway in the dentate gyrus by in vivo dopamine D1 receptor stimulation requires glutamatergic transmission. Neuropharmacology 63, 1107-1117. doi: 10.1016/j.neuropharm.2012.06.062
45. Geranton, S. M., Jimenez-Diaz, L., Torsney, C., Tochiki, K. K., Stuart, S. A., Leith, J. L., et al. (2009). A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states. J. Neurosci. 29, 15017-15027. doi: 10.1523/JNEUROSCI.3451-09.2009
46. Gobert, D., Topolnik, L., Azzi, M., Huang, L., Badeaux, F., Desgroseillers, L., et al. (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, 1160-1174. doi: 10.1111/j.1471-4159.2008.05470.x
47. Gong, Y., Ishida-Takahashi, R., Villanueva, E. C., Fingar, D. C., Munzberg, H., and Myers, M. G. Jr. (2007). The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. J. Biol. Chem. 282, 31019-31027. doi: 10.1074/jbc.M702838200
48. Greengard, P. (2001). The neurobiology of dopamine signaling. Biosci. Rep. 21, 247-269. doi: 10.1023/A:1013205230142
49. Gressner, A. M., and Wool, I. G. (1974). The phosphorylation of liver ribosomal proteins in vivo. Evidence that only a single small subunit protein (S6) is phosphorylated. J. Biol. Chem. 249, 6917-6925.
50. Gu, Q. H., Yu, D., Hu, Z., Liu, X., Yang, Y., Luo, Y., et al. (2015). miR-26a and miR-384-5p are required for LTP maintenance and spine enlargement. Nat. Commun. 6, 6789. doi: 10.1038/ncomms7789
51. Guegan, T., Cutando, L., Gangarossa, G., Santini, E., Fisone, G., Martinez, A., et al. (2013). Operant behavior to obtain palatable food modifies ERK activity in the brain reward circuit. Eur. Neuropsychopharmacol. 23, 240-252. doi: 10.1016/j.euroneuro.2012.04.009
52. Harter, P. N., Jennewein, L., Baumgarten, P., Ilina, E., Burger, M. C., Thiepold, A.L., et al. (2015). Immunohistochemical assessment of phosphorylated mTORC1-pathway proteins in human brain tumors. PLoS ONE 10:e0127123. doi: 10.1371/journal.pone.0127123
53. Heidenreich, K. A., and Toledo, S. P. (1989). Insulin receptors mediate growth effects in cultured fetal neurons. II. Activation of a protein kinase that phosphorylates ribosomal protein S6. Endocrinology 125, 1458-1463. doi: 10.1210/endo-125-3-1458
54. /-monophosphate- regulated phosphoprotein enriched in dopamine-innervated brain regions. II. Purification and characterization of the phosphoprotein from bovine caudate nucleus. J. Neurosci. 4, 99-110.
55. House, C., Wettenhall, R. E., and Kemp, B. E. (1987). The influence of basic residues on the substrate specificity of protein kinase C. J. Biol. Chem. 262, 772-777.
56. Huang, X., Zhang, H., Yang, J., Wu, J., McMahon, J., Lin, Y., et al. (2010). Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol. Dis. 40, 193-199. doi: 10.1016/j.nbd.2010.05.024
57. Hutchinson, J. A., Shanware, N. P., Chang, H., and Tibbetts, R. S. (2011). Regulation of ribosomal protein S6 phosphorylation by casein kinase 1 and protein phosphatase 1. J. Biol. Chem. 286, 8688-8696. doi: 10.1074/jbc.M110.141754
58. Ishizuka, Y., Kakiya, N., Nawa, H., and Takei, N. (2008). Leucine induces phosphorylation and activation of p70S6K in cortical neurons via the system L amino acid transporter. J. Neurochem. 106, 934-942. doi: 10.1111/j.1471-4159.2008.05438.x
59. Iyer, A. M., van Scheppingen, J., Milenkovic, I., Anink, J. J., Adle-Biassette, H., Kovacs, G. G., et al. (2014). mTOR Hyperactivation in down syndrome hippocampus appears early during development. J. Neuropathol. Exp. Neurol. 73, 671-683. doi: 10.1097/NEN.0000000000000083
60. Jansen, F. E., Notenboom, R. G., Nellist, M., Goedbloed, M. A., Halley, D. J., de Graan, P. N., et al. (2004). Differential localization of hamartin and tuberin and increased S6 phosphorylation in a tuber. Neurology 63, 1293-1295. doi: 10.1212/01.WNL.0000140702.08902.D7
61. Jansen, L. A., Mirzaa, G. M., Ishak, G. E., O'Roak, B. J., Hiatt, J. B., Roden, W. H., et al. (2015). PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain 138, 1613-1628. doi: 10.1093/brain/awv045
62. Kelleher, R. J. III, Govindarajan, A., Jung, H. Y., Kang, H., and Tonegawa, S. (2004). Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116,467-479. doi: 10.1016/S0092-8674(04)00115-1
63. Kim, J. Y., Duan, X., Liu, C. Y., Jang, M. H., Guo, J. U., Pow-Anpongkul, N., et al. (2009). DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron 63, 761-773. doi: 10.1016/j.neuron.2009.08.008
64. Kim, S. H., Park, H. G., Kim, H. S., Ahn, Y. M., and Kim, Y. S. (2010). Effects of neonatal MK-801 treatment on p70S6K-S6/eIF4B signal pathways and protein translation in the frontal cortex of the developing rat brain. Int. J. Neuropsychopharmacol. 13, 1233-1246. doi: 10.1017/S1461145709991192
65. Kim, S. H., Yu, H. S., Park, H. G., Ha, K., Kim, Y. S., Shin, S. Y., et al. (2013). Intracerebroventricular administration of ouabain, a Na/K-ATPase inhibitor, activates mTOR signal pathways and protein translation in the rat frontal cortex. Prog. Neuropsychopharmacol. Biol. Psychiatry 45, 73-82. doi: 10.1016/j.pnpbp.2013.04.018
66. Kim, T. S., Jang, C. Y., Kim, H. D., Lee, J. Y., Ahn, B. Y., and Kim, J. (2006). Interaction of Hsp90 with ribosomal proteins protects from ubiquitination and proteasome-dependent degradation. Mol. Biol. Cell 17, 824-833. doi: 10.1091/mbc.E05-08-0713
67. Kim, Y. K., Kim, S., Shin, Y. J., Hur, Y. S., Kim, W. Y., Lee, M. S., et al. (2014). Ribosomal protein S6, a target of rapamycin, is involved in the regulation of rRNA genes by possible epigenetic changes in Arabidopsis. J. Biol. Chem. 289, 3901-3912. doi: 10.1074/jbc.M113.515015
68. Klann, E., and Dever, T. E. (2004). Biochemical mechanisms for translational regulation in synaptic plasticity. Nat. Rev. Neurosci. 5, 931-942. doi: 10.1038/nrn1557
69. Knight, Z. A., Tan, K., Birsoy, K., Schmidt, S., Garrison, J. L., Wysocki, R. W., et al. (2012). Molecular profiling of activated neurons by phosphorylated ribosome capture. Cell 151, 1126-1137. doi: 10.1016/j.cell.2012.10.039
70. Koh, P. O. (2013). Ferulic acid attenuates focal cerebral ischemia-induced decreases in p70S6 kinase and S6 phosphorylation. Neurosci. Lett. 555, 7-11. doi: 10.1016/j.neulet.2013.09.001
71. Kressler, D., Hurt, E., and Bassler, J. (2010). Driving ribosome assembly. Biochim. Biophys. Acta 1803, 673-683. doi: 10.1016/j.bbamcr.2009.10.009
72. Krieg, J., Hofsteenge, J., and Thomas, G. (1988). Identification of the 40 S ribosomal protein S6 phosphorylation sites induced by cycloheximide. J. Biol. Chem. 263, 11473-11477.
73. Kroczynska, B., Kaur, S., Katsoulidis, E., Majchrzak-Kita, B., Sassano, A., Kozma, S. C., et al. (2009). Interferon-dependent engagement of eukaryotic initiation factor 4B via S6 kinase (S6K)- and ribosomal protein S6K- mediated signals. Mol. Cell. Biol. 29, 2865-2875. doi: 10.1128/MCB.01537-08
74. Kruppa, J., and Clemens, M. J. (1984). Differential kinetics of changes in the state of phosphorylation of ribosomal protein S6 and in the rate of protein synthesis in MPC 11 cells during tonicity shifts. EMBO J. 3, 95-100.
75. Kwon, C. H., Luikart, B. W., Powell, C. M., Zhou, J., Matheny, S. A., Zhang, W., et al. (2006). Pten regulates neuronal arborization and social interaction in mice. Neuron 50, 377-388. doi: 10.1016/j.neuron.2006.03.023
76. Kwon, C. H., Zhu, X., Zhang, J., and Baker, S. J. (2003). mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. Proc. Natl. Acad. Sci. U.S.A. 100, 12923-12928. doi: 10.1073/pnas.2132711100
77. Lai, K. O., Liang, Z., Fei, E., Huang, H., and Ip, N. Y. (2015). Cyclin-dependent kinase 5 (Cdk5)-dependent phosphorylation of p70 ribosomal S6 kinase 1 (S6K) is required for dendritic spine morphogenesis. J. Biol. Chem. 290, 14637-14646. doi: 10.1074/jbc.M114.627117
78. Lai, K. O., Wong, A. S., Cheung, M. C., Xu, P., Liang, Z., Lok, K. C., et al. (2011). TrkB phosphorylation by Cdk5 is required for activity-dependent structural plasticity and spatial memory. Nat. Neurosci. 15, 1506-1515. doi: 10.1038/nn.3237
79. Lastick, S. M., Nielsen, P. J., and McConkey, E. H. (1977). Phosphorylation of ribosomal protein S6 in suspension cultured HeLa cells. Mol. Gen. Genet. 152, 223-230. doi: 10.1007/BF00693074
80. Lee, J. H., Tecedor, L., Chen, Y. H., Monteys, A. M., Sowada, M. J., Thompson, L. M., et al. (2015). Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron 85, 303-315. doi: 10.1016/j.neuron.2014.12.019
81. Lempiainen, H., and Shore, D. (2009). Growth control and ribosome biogenesis. Curr. Opin. CellBiol. 21,855-863. doi: 10.1016/j.ceb.2009.09.002
82. Lenz, G., and Avruch, J. (2005). Glutamatergic regulation of the p70S6 kinase in primary mouse neurons. J. Biol. Chem. 280, 38121-38124. doi: 10.1074/jbc.C500363200
83. Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K., and Avruch, J. (2005). Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702-713. doi: 10.1016/j.cub.2005.02.053
84. Lugo, J. N., Smith, G. D., Morrison, J. B., and White, J. (2013). Deletion of PTEN produces deficits in conditioned fear and increases fragile X mental retardation protein. Learn. Mem. 20, 670-673. doi: 10.1101/lm.032839.113
85. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P., and Pandolfi, P. P. (2005). Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179-193. doi: 10.1016/j.cell.2005.02.031
86. Macias, M., Blazejczyk, M., Kazmierska, P., Caban, B., Skalecka, A., Tarkowski, A, et al. (2013). Spatiotemporal characterization of mTOR kinase activity following kainic acid induced status epilepticus and analysis of rat brain response to chronic rapamycin treatment. PLoS ONE 8:e64455. doi: 10.1371/journal.pone.0064455
87. Magri, L., Cambiaghi, M., Cominelli, M., Alfaro-Cervello, C., Cursi, M., Pala, M., et al. (2011). Sustained activation of mTOR pathway in embryonic neural stem cells leads to development oftuberous sclerosis complex-associated lesions. Cell Stem Cell 9, 447-462. doi: 10.1016/j.stem.2011.09.008
88. Mahoney, S. J., Dempsey, J. M., and Blenis, J. (2009). Cell signaling in protein synthesis ribosome biogenesis and translation initiation and elongation. Prog. Mol. Biol. Transl. Sci. 90, 53-107. doi: 10.1016/S1877-1173(09)90002-3
89. Martin, K. A., Schalm, S. S., Romanelli, A., Keon, K. L., and Blenis, J. (2001). Ribosomal S6 kinase 2 inhibition by a potent C-terminal repressor domain is relieved by mitogen-activated protein-extracellular signal-regulated kinase kinase-regulated phosphorylation. J. Biol. Chem. 276, 7892-7898. doi: 10.1074/jbc.M009972200
90. Martin-Perez, J., and Thomas, G. (1983). Ordered phosphorylation of 40S ribosomal protein S6 after serum stimulation of quiescent 3T3 cells. Proc. Natl. Acad. Sci. U.S.A. 80, 926-930. doi: 10.1073/pnas.80.4.926
91. Mazei-Robison, M. S., Koo, J. W., Friedman, A. K., Lansink, C. S., Robison, A. J., Vinish, M., et al. (2011). Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons. Neuron 72, 977-990. doi: 10.1016/j.neuron.2011.10.012
92. Mazumder, B., Sampath, P., Seshadri, V., Maitra, R. K., Dicorleto, P. E., and Fox, P. L. (2003). Regulated release of L13a from the 60S ribosomal subunit as a mechanism of transcript-specific translational control. Cell 115, 187-198. doi: 10.1016/S0092-8674(03)00773-6
93. McMahon, J., Huang, X., Yang, J., Komatsu, M., Yue, Z., Qian, J., et al. (2011). Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis. J. Neurosci. 32, 15704-15714. doi: 10.1523/JNEUROSCI.2392-12.2012
94. Meffre, J., Chaumont-Dubel, S., Mannoury la Cour, C., Loiseau, F., Watson, D. J., Dekeyne, A., et al. (2012). 5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia. EMBO Mol. Med. 4, 1043-1056. doi: 10.1002/emmm.201201410
95. Meikle, L., Talos, D. M., Onda, H., Pollizzi, K., Rotenberg, A., Sahin, M., et al. (2007). A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J. Neurosci. 27, 5546-5558. doi: 10.1523/JNEUROSCI.5540-06.2007
96. Meyuhas, O. (2008). Physiological roles of ribosomal protein S6: one of its kind. Int. Rev. Cell Mol. Biol. 268, 1-37. doi: 10.1016/S1937-6448(08)00801-0
97. Meyuhas, O. (2015). Ribosomal protein S6 phosphorylation: four decades of research. Int. Rev. CellMol. Biol. 320,41-73. doi: 10.1016/bs.ircmb.2015.07.006
98. Montgomery, S. A., Berglund, P., Beard, C. W., and Johnston, R. E. (2006). Ribosomal protein S6 associates with alphavirus nonstructural protein 2 and mediates expression from alphavirus messages. J. Virol. 80, 7729-7739. doi: 10.1128/JVI.00425-06
99. Moore, C. E., Xie, J., Gomez, E., and Herbert, T. P. (2009). Identification of cAMP- dependent kinase as a third in vivo ribosomal protein S6 kinase in pancreatic beta-cells. J.Mol. Biol. 389,480-494. doi: 10.1016/j.jmb.2009.04.020
100. Mukhopadhyay, N. K., Price, D. J., Kyriakis, J. M., Pelech, S., Sanghera, J., and Avruch, J. (1992). An array of insulin-activated, proline-directed serine/threonine protein kinases phosphorylate the p70 S6 kinase. J. Biol. Chem. 267, 3325-3335.
101. Norsted Gregory, E., Codeluppi, S., Gregory, J. A., Steinauer, J., and Svensson, A.I. (2010). Mammalian target of rapamycin in spinal cord neurons mediates hypersensitivity induced by peripheral inflammation. Neuroscience 169, 1392-1402. doi: 10.1016/j.neuroscience.2010.05.067
102. Nygard, O., and Nilsson, L. (1990). Translational dynamics. Interactions between the translational factors, tRNA and ribosomes during eukaryotic protein synthesis. Eur. J. Biochem. 191, 1-17. doi: 10.1111/j.1432-1033.1990.tb19087.x
103. Parker, W. E., Orlova, K. A., Heuer, G. G., Baybis, M., Aronica, E., Frost, M., et al. (2011). Enhanced epidermal growth factor, hepatocyte growth factor, and vascular endothelial growth factor expression in tuberous sclerosis complex. Am. J. Pathol. 178,296-305.doi: 10.1016/j.ajpath.2010.11.031
104. Patursky-Polischuk, I., Stolovich-Rain, M., Hausner-Hanochi, M., Kasir, J., Cybulski, N., Avruch, J., et al. (2009). The TSC-mTOR pathway mediates translational activation of TOP mRNAs by insulin largely in a raptor- or rictor-independent manner. Mol. Cell. Biol. 29, 640-649. doi: 10.1128/MCB.00980-08
105. /-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol. Cell. Biol. 24, 3112-3124. doi: 10.1128/MCB.24.8.3112-3124.2004
106. Proulx, K., Cota, D., Woods, S. C., and Seeley, R. J. (2008). Fatty acid synthase inhibitors modulate energy balance via mammalian target of rapamycin complex1 signaling in the central nervous system. Diabetes 57, 3231-3238. doi: 10.2337/db07-1690
107. Puighermanal, E., Marsicano, G., Busquets-Garcia, A., Lutz, B., Maldonado, R., and Ozaita, A. (2009). Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nat. Neurosci. 12, 1152-1158. doi: 10.1038/nn.2369
108. Rapanelli, M., Frick, L. R., Pogorelov, V., Ota, K. T., Abbasi, E., Ohtsu, G., et al. (2014). Dysregulated intracellular signaling in the striatum in a pathophysiologically grounded model of Tourette syndrome. Eur. Neuropsychopharmacol. 24, 1896-1906. doi: 10.1016/j.euroneuro.2014.10.007
109. Ravikumar, B., Vacher, C., Berger, Z., Davies, J. E., Luo, S., Oroz, L.G., et al. (2004). Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585-595. doi: 10.1038/ng1362
110. Ricciardi, S., Boggio, E. M., Grosso, S., Lonetti, G., Forlani, G., Stefanelli, G., et al. (2010). Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum. Mol. Genet. 20, 1182-1196. doi: 10.1093/hmg/ddq563
111. Roberts, S., and Morelos, B. S. (1979). Phosphorylation ofmultiple proteins ofboth ribosomal subunits in rat cerebral cortex in vivo. Effect of adenosine 3>:5>-cyclic monophosphate. Biochem. J. 184, 233-244. doi: 10.1042/bj1840233
112. Roux, P. P., and Blenis, J. (2004). ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev. 68, 320-344. doi: 10.1128/MMBR.68.2.320-344.2004
113. Roux, P. P., Shahbazian, D., Vu, H., Holz, M. K., Cohen, M. S., Taunton, J., et al. (2007). RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J. Biol. Chem. 282, 14056-14064. doi: 10.1074/jbc.M700906200
114. Rozas, N. S., Redell, J. B., Mckenna, J. III, Moore, A. N., Gambello, M. J., and Dash, P. K. (2015). Prolonging the survival of Tsc2 conditional knockout mice byglutamine supplementation. Biochem. Biophys. Res. Commun. 457, 635-639. doi: 10.1016/j.bbrc.2015.01.039
115. Ruvinsky, I., Sharon, N., Lerer, T., Cohen, H., Stolovich-Rain, M., Nir, T., et al. (2005). Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev. 19, 2199-2211. doi: 10.1101/gad.351605
116. Salles, M. J., Herve, D., Rivet, J. M., Longueville, S., Millan, M. J., Girault, J. A., et al. (2013). Transient and rapid activation of Akt/GSK-3beta and mTORC1 signaling by D3 dopamine receptor stimulation in dorsal striatum and nucleus accumbens. J.Neurochem. 125,532-544. doi: 10.1111/jnc.12206
117. Santini, E., Feyder, M., Gangarossa, G., Bateup, H. S., Greengard, P., and Fisone, G. (2012). Dopamine- and cAMP-regulated phosphoprotein of 32-kDa (DARPP-32)-dependent activation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) signaling in experimental parkinsonism. J. Biol. Chem. 287, 27806-27812. doi: 10.1074/jbc.M112.388413
118. Santini, E., Heiman, M., Greengard, P., Valjent, E., and Fisone, G. (2009). Inhibition of mTOR signaling in Parkinson's disease prevents L-DOPA-induced dyskinesia. Sci. Signal. 2:ra36. doi: 10.1126/scisignal.2000308
119. Santini, E., Sgambato-Faure, V., Li, Q., Savasta, M., Dovero, S., Fisone, G., et al. (2010). Distinct changes in cAMP and extracellular signal-regulated protein kinase signalling in L-DOPA-induced dyskinesia. PLoS ONE 5:e12322. doi: 10.1371/journal.pone.0012322
120. Saraf, A., Luo, J., Morris, D. R., and Storm, D. R. (2014). Phosphorylation of eukaryotic translation initiation factor 4E and eukaryotic translation initiation factor 4E-binding protein (4EBP) and their upstream signaling components undergo diurnal oscillation in the mouse hippocampus: implications for memory persistence. J. Biol. Chem. 289, 20129-20138. doi: 10.1074/jbc.M114.552638
121. Schumacher, A. M., Velentza, A. V., Watterson, D. M., and Dresios, J. (2005). Death-associated protein kinase phosphorylates mammalian ribosomal protein S6 and reduces protein synthesis. Biochemistry 45, 13614-13621. doi: 10.1021/bi060413y
122. Son, O., Kim, S., Shin, Y. J., Kim, W. Y., Koh, H. J., and Cheon, C. I. (2015). Identification of nucleosome assembly protein 1 (NAP1) as an interacting partner of plant ribosomal protein S6 (RPS6) and a positive regulator of rDNA transcription. Biochem. Biophys. Res. Commun. 465, 200-205. doi: 10.1016/j.bbrc.2015.07.150
123. Stolovich, M., Tang, H., Hornstein, E., Levy, G., Cohen, R., Bae, S. S., et al. (2002). Transduction of growth or mitogenic signals into translational activation of TOP mRNAs is fully reliant on the phosphatidylinositol 3-kinase-mediated pathway but requires neither S6K1 nor rpS6 phosphorylation. Mol. Cell. Biol. 22,8101-8113. doi: 10.1128/MCB.22.23.8101-8113.2002
124. Sun, J., Liu, Y., Moreno, S., Baudry, M., and Bi, X. (2015). Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function. J. Neurosci. 35, 4706-4718. doi: 10.1523/JNEUROSCI.4276-14.2015
125. Sun, Y. X., Ji, X., Mao, X., Xie, L., Jia, J., Galvan, V., et al. (2014). Differential activation of mTOR complex 1 signaling in human brain with mild to severe Alzheimer's disease. J.AlzheimersDis. 38,437-444. doi: 10.3233/JAD-131124
126. Sutton, L. P., and Caron, M. G. (2015). Essential role of D1R in the regulation of mTOR complex1 signaling induced by cocaine. Neuropharmacology 99, 610-619. doi: 10.1016/j.neuropharm.2015.08.024
127. Takei, N., Inamura, N., Kawamura, M., Namba, H., Hara, K., Yonezawa, K., et al. (2004). Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J. Neurosci. 24, 9760-9769. doi: 10.1523/JNEUROSCI.1427-04.2004
128. Tang, H., Hornstein, E., Stolovich, M., Levy, G., Livingstone, M., Templeton, D., et al. (2001). Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinase-mediated signaling, is partially inhibited by rapamycin, and is independent of S6K1 and rpS6 phosphorylation. Mol. Cell. Biol. 21, 8671-8683. doi: 10.1128/MCB.21.24.8671-8683.2001
129. Tas, P. W., and Martini, O. H. (1987). Are highly phosphorylated 40-S subunits preferentially utilized during protein synthesis in a cell-free system from HeLa cells? Eur. J. Biochem. 163, 561-567. doi: 10.1111/j.1432-1033.1987.tb10904.x
130. Tedesco, V., Ravagnani, C., Bertoglio, D., and Chiamulera, C. (2013). Acute ketamine-induced neuroplasticity: ribosomal protein S6 phosphorylation expression in drug addiction-related rat brain areas. Neuroreport 24, 388-393. doi: 10.1097/WNR.0b013e32836131ad
131. Tedesco, V., Roquet, R. F., DeMis, J., Chiamulera, C., and Monfils, M. H. (2014). Extinction, applied after retrieval of auditory fear memory, selectively increases zinc-finger protein 268 and phosphorylated ribosomal protein S6 expression in prefrontal cortex and lateral amygdala. Neurobiol. Learn. Mem. 115, 78-85. doi: 10.1016/j.nlm.2014.08.015
132. Thomanetz, V., Angliker, N., Cloetta, D., Lustenberger, R. M., Schweighauser, M., Oliveri, F., et al. (2013). Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. J. Cell Biol. 201, 293-308. doi: 10.1083/jcb.201205030
133. Thomas, G., Martin-Perez, J., Siegmann, M., and Otto, A. M. (1982). The effect of serum, EGF, PGF2 alpha and insulin on S6 phosphorylation and the initiation of protein and DNA synthesis. Cell 30, 235-242. doi: 10.1016/0092-8674(82)90029-0
134. Troca-Marin, J. A., Alves-Sampaio, A., and Montesinos, M. L. (2011). An increase in basal BDNF provokes hyperactivation of the Akt-mammalian target of rapamycin pathway and deregulation of local dendritic translation in a mouse model of Down's syndrome. J. Neurosci. 31, 9445-9455. doi: 10.1523/JNEUROSCI.0011-11.2011
135. Tsai, P. T., Hull, C., Chu, Y., Greene-Colozzi, E., Sadowski, A. R., Leech, J. M., et al. (2010). Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488, 647-651. doi: 10.1038/nature11310
136. Tsokas, P., Grace, E. A., Chan, P., Ma, T., Sealfon, S. C., Iyengar, R., et al. (2005). Local protein synthesis mediates a rapid increase in dendritic elongation factor 1A after induction of late long-term potentiation. J. Neurosci. 25, 5833-5843. doi: 10.1523/JNEUROSCI.0599-05.2005
137. Tsokas, P., Ma, T., Iyengar, R., Landau, E. M., and Blitzer, R. D. (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, 5885-5894. doi: 10.1523/JNEUROSCI.4548-06.2007
138. Tsujimura, K., Irie, K., Nakashima, H., Egashira, Y., Fukao, Y., Fujiwara, M., et al. (2015). miR-199a links MeCP2 with mTOR signaling and its dysregulation leads to rett syndrome phenotypes. Cell Rep. 12, 1887-1901. doi: 10.1016/j.celrep.2015.08.028
139. Valjent, E., Bertran-Gonzalez, J., Bowling, H., Lopez, S., Santini, E., Matamales, M., et al. (2011). Haloperidol regulates the state of phosphorylation of ribosomal protein S6 via activation of PKA and phosphorylation of DARPP-32. Neuropsychopharmacology 36, 2561-2570. doi: 10.1038/npp.2011.144
140. Villanueva, E. C., Munzberg, H., Cota, D., Leshan, R. L., Kopp, K., Ishida- Takahashi, R., et al. (2009). Complex regulation of mammalian target of rapamycin complex 1 in the basomedial hypothalamus by leptin and nutritional status. Endocrinology 150, 4541-4551. doi: 10.1210/en.2009-0642
141. Vinnikov, I. A., Hajdukiewicz, K., Reymann, J., Beneke, J., Czajkowski, R., Roth, L.B, et al. (2014). Hypothalamic miR-103 protects from hyperphagic obesity in mice. J. Neurosci. 34, 10659-10674. doi: 10.1523/JNEUROSCI.4251-13.2014
142. Wang, X., Luo, Y. X., He, Y. Y., Li, F. Q., Shi, H. S., Xue, L. F., et al. (2010). Nucleus accumbens core mammalian target of rapamycin signaling pathway is critical for cue-induced reinstatement of cocaine seeking in rats. J. Neurosci. 30, 12632-12641. doi: 10.1523/JNEUROSCI.1264-10.2010
143. Warner, J. R., and McIntosh, K. B. (2009). How common are extraribosomal functions of ribosomal proteins? Mol. Cell 34, 3-11. doi: 10.1016/j.molcel.2009.03.006
144. Way, S. W., Mckenna, J. III, Mietzsch, U., Reith, R. M., Wu, H. C., and Gambello, M. J. (2009). Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse. Hum. Mol. Genet. 18,1252-1265. doi: 10.1093/hmg/ddp025
145. Wettenhall, R. E., Erikson, E., and Maller, J. L. (1992). Ordered multisite phosphorylation ofXenopus ribosomal protein S6 byS6 kinase II. J. Biol. Chem. 267, 9021-9027.
146. Wool, I. G. (1996). Extraribosomal functions of ribosomal proteins. Trends Biochem. Sci. 21, 164-165. doi: 10.1016/S0968-0004(96)20011-8
147. Wu, J., McCallum, S. E., Glick, S. D., and Huang, Y. (2011). Inhibition of the mammalian target of rapamycin pathway by rapamycin blocks cocaine-induced locomotor sensitization. Neuroscience 172, 104-109. doi: 10.1016/j.neuroscience.2010.10.041
148. Xia, T., Cheng, Y., Zhang, Q., Xiao, F., Liu, B., Chen, S., et al. (2012). S6K1 in the central nervous system regulates energy expenditure via MC4R/CRH pathways in response to deprivation of an essential amino acid. Diabetes 61, 2461-2471. doi: 10.2337/db11-1278
149. Xiao, H., Wang, H., Silva, E. A., Thompson, J., Guillou, A., Yates, J. R. Jr., et al. (2015). The Pallbearer E3 ligase promotes actin remodeling via RAC in efferocytosis by degrading the ribosomal protein S6. Dev. Cell 32, 19-30. doi: 10.1016/j.devcel.2014.11.015
150. Xiong, X., Xie, R., Zhang, H., Gu, L., Xie, W., Cheng, M., et al. (2014). PRAS40 plays a pivotal role in protecting against stroke by linking the Akt and mTOR pathways. Neurobiol. Dis. 66, 43-52. doi: 10.1016/j.nbd.2014.02.006
151. Xue, S., and Barna, M. (2012). Specialized ribosomes: a new frontier in gene regulation and organismal biology. Nat. Rev. Mol. Cell Biol. 13, 355-369. doi: 10.1038/nrm3359
152. Yang, W., Jiang, W., Luo, L., Bu, J., Pang, D., Wei, J., et al. (2014). Genetic deletion of Rheb1 in the brain reduces food intake and causes hypoglycemia with altered peripheral metabolism. Int. J. Mol. Sci. 15, 1499-1510. doi: 10.3390/ijms15011499
153. Yano, T., Ferlito, M., Aponte, A. M., Kuno, A., Miura, T., Murphy, E., et al. (2013). Pivotal role of mTORC2 and involvement of ribosomal protein S6 in cardioprotective signaling. Circ. Res. 114, 1268-1280. doi: 10.1161/CIRCRESAHA.114.303562
154. Yoon, S. C., Seo, M. S., Kim, S. H., Jeon, W. J., Ahn, Y. M., Kang, U. G., et al. (2008). The effect of MK-801 on mTOR/p70S6K and translation-related proteins in rat frontal cortex. Neurosci. Lett. 434, 23-28. doi: 10.1016/j.neulet.2008.01.020
155. Yu, J. J., Zhang, Y., Wang, Y., Wen, Z. Y., Liu, X. H., Qin, J., et al. (2013). Inhibition of calcineurin in the prefrontal cortex induced depressive-like behavior through mTOR signaling pathway. Psychopharmacology (Berl). 225, 361-372. doi: 10.1007/s00213-012-2823-9
156. Zeng, L. H., Rensing, N. R., and Wong, M. (2009). The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J. Neurosci. 29, 6964-6972. doi: 10.1523/JNEUROSCI.0066-09.2009
157. Zeng, L. H., Rensing, N. R., Zhang, B., Gutmann, D. H., Gambello, M. J., and 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. 20,445-454. doi: 10.1093/hmg/ddq491
158. Zeng, L. H., Xu, L., Gutmann, D. H., and Wong, M. (2008). Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol. 63, 444-453. doi: 10.1002/ana.21331
159. Zhang, B., and Wong, M. (2012). Pentylenetetrazole-induced seizures cause acute, but not chronic, mTOR pathway activation in rat. Epilepsia 53, 506-511. doi: 10.1111/j.1528-1167.2011.03384.x
160. Zhou, J., Blundell, J., Ogawa, S., Kwon, C. H., Zhang, W., Sinton, C., et al. (2009). Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J. Neurosci. 29, 1773-1783. doi: 10.1523/JNEUROSCI.5685-08.2009
161. Zhou, M., Li, W., Huang, S., Song, J., Kim, J. Y., Tian, X., et al. (2013). mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons. Neuron 77, 647-654. doi: 10.1016/j.neuron.2012.12.033
162. Zou, J., Zhou, L., Du, X. X., Ji, Y., Xu, J., Tian, J., et al. (2011). Rheb1 is required for mTORC1 and myelination in postnatal brain development. Dev. Cell 20, 97-108. doi: 10.1016/j.devcel.2010.11.020