Abstract
Neuronal development and synaptic plasticity are highly regulated processes in which protein kinases play a key role. Recently, increasing attention has been paid to a serine/threonine protein kinase called mammalian target of rapamycin (mTOR) that has well-known functions in cell proliferation and growth. In neuronal cells, mTOR is implicated in multiple processes, including transcription, ubiquitin-dependent proteolysis, and microtubule and actin dynamics, all of which are crucial for neuronal development and long-term modification of synaptic strength. The aim of this article is to present our current understanding of mTOR functions in axon guidance, dendritic tree development, formation of dendritic spines, and in several forms of long-term synaptic plasticity. We also aim to present explanation for the mTOR effects on neurons at the level of mTOR-regulated genes and proteins.
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Wu, G. Y., Deisseroth, K., and Tsien, R. W. (2001) Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology. Nat. Neurosci. 4, 151–158.
Adams, J. P., and Sweatt, J. D. (2002) Molecular psychology: roles for the ERK MAP kinase cascade in memory. Annu. Rev. Pharmacol. Toxicol. 42, 135–163.
Atwal, J. K., Massie, B., Miller, F. D., and Kaplan, D. R. (2000) The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron 27, 265–277.
Sanna, P. P., Cammalleri, M., Berton, F., et al. (2002) Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region. J. Neurosci. 22, 3359–3365.
Jaworski, J., Spangler, S., Seeburg, D. P., Hoogenraad, C. C., and Sheng, M. (2005) Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J. Neurosci. 25, 11,300–11,312.
Kumar, V., Zhang, M. X., Swank, M. W., Kunz, J., and Wu, G. Y. (2005) Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J. Neurosci. 25, 11,288–11,299.
Fink, C. C., Bayer, K. U., Myers, J. W., Ferrell, J. E., Jr., Schulman, H., and Meyer, T. (2003) Selective regulation of neurite extension and synapse formation by the beta but not the alpha isoform of CaMKII. Neuron 39, 283–297.
Jourdain, P., Fukunaga, K., and Muller, D. (2003) Calcium/calmodulin-dependent protein kinase II contributes to activity-dependent filopodia growth and spine formation. J. Neurosci. 23, 10,645–10,649.
Colbran, R. J., and Brown, A. M. (2004) Calcium/calmodulin-dependent protein kinase II and synaptic plasticity. Curr. Opin. Neurobiol. 14, 318–327.
Redmond, L., Kashani, A. H., and Ghosh, A. (2002) Calcium regulation of dendritic growth via CaM kinase IV and CREB-mediated transcription. Neuron 34, 999–1010.
Wu, G. Y., and Cline, H. T. (1998) Stabilization of dendritic arbor structure in vivo by CaMKII. Science 279, 222–226.
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. USA 100, 12,923–12,928.
Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H., and Sabatini, D. M. (1998) RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc. Natl. Acad. Sci. USA 95, 1432–1437.
Xie, M. W., Jin, F., Hwang, H., et al. (2005) Insights into TOR function and rapamycin response: chemical genomic profiling by using a high-density cell array method. Proc. Natl. Acad. Sci. USA 102, 7215–7220.
Chan, T. F., Carvalho, J., Riles, L., and Zheng, X. F. (2000) A chemical genomics approach toward understanding the global functions of the target of rapamycin protein (TOR). Proc. Natl. Acad. Sci. USA 97, 13,227–13,232.
Guertin, D. A., Guntur, K. V., Bell, G. W., Thoreen, C. C., and Sabatini, D. M. (2006) Functional genomics identifies TOR-regulated genes that control growth and division. Curr. Biol. 16, 958–970.
Jacinto, E., and Hall, M. N. (2003) Tor signalling in bugs, brain and brawn. Nat. Rev. Mol. Cell Biol. 4, 117–126.
Sarbassov dos, D., Ali, S. M., and Sabatini, D. M. (2005) Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 17, 596–603.
Schmelzle, T., and Hall, M. N. (2000). TOR, a central controller of cell growth. Cell 103, 253–262.
Harris, T. E., and Lawrence, J. C., Jr. (2003) TOR signaling. Sci. STKE 2003, re15.
Lenz, G., and Avruch, J. (2005) Glutamatergic regulation of the p70S6 kinase in primary mouse neurons. J. Biol. Chem. 280, 38121–38124.
Cammalleri, M., Lutjens, R., Berton, F., et al. (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. USA 100, 14,368–14,373.
Hou, L., and Klann, E. (2004) Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J. Neurosci. 24, 6352–6361.
Garami, A., Zwartkruis, F. J., Nobukuni, T., et al. (2003) Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11, 1457–1466.
Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C., and Blenis, J. (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268.
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., and Cantley, L. C. (2002) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151–162.
Fang, Y., Vilella-Bach, M., Bachmann, R., Flanigan, A., and Chen, J. (2001) Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 294, 1942–1945.
Tee, A. R., Anjum, R., and Blenis, J. (2003) Inactivation of the tuberous sclerosis complex-1 and-2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and-independent phosphorylation of tuberin. J. Biol. Chem. 278, 37,288–37,296.
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.
Kimura, N., Tokunaga, C., Dalal, S., et al. (2003) A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 8, 65–79.
Sarbassov, D. D., Ali, S. M., Kim, D. H., et al. (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol 14, 1296–1302.
Hara, K., Maruki, Y., Long, X., et al. (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 100, 177–189.
Kim, D. H., sarbassov, D. D., Ali, S. et al. (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175.
Hara, K., Yonezawa, K., Kozlowski, M. T., et al. (1997) Regulation of eIF-4E BP1 phosphorylation by mTOR. J. Biol. Chem. 272, 26,457–26,463.
Jefferies, H. B., Fumagalli, S., Dennis, P. B., Reinhard, C., Pearson, R. B., and Thomas, G. (1997) Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k. EMBO J. 16, 3693–3704.
Meyuhas, O. (2000) Synthesis of the translational apparatus is regulated at the translational level. Eur. J. Biochem. 267, 6321–6330.
Beretta, L., Gingras, A. C., Svitkin, Y. V., Hall, M. N., and Sonenberg, N. (1996) Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J. 15, 658–664.
Peterson, R. T., Desai, B. N., Hardwick, J. S., and Schreiber, S. L. (1999) Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Proc. Natl. Acad. Sci. USA 96, 4438–4442.
Choi, J. H., Bertram, P. G., Drenan, R., Carvalho, J., Zhou, H. H., and Zheng, X. F. (2002) The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase. EMBO Rep. 3, 988–994.
Redpath, N. T., Foulstone, E. J., and Proud, C. G. (1996) Regulation of translation elongation factor-2 by insulin via a rapamycin-sensitive signalling pathway. EMBO J. 15, 2291–2297.
Azpiazu, I., Saltiel, A. R., DePaoli-Roach, A. A., and Lawrence, J. C. (1996) Regulation of both glycogen synthase and PHAS-I by insulin in rat skeletal muscle involves mitogen-activated protein kinase-independent and rapamycin-sensitive pathways. J. Biol. Chem. 271, 5033–5039.
Shepherd, P. R., Nave, B. T., and Siddle, K. (1995) Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3-L1 adipocytes: evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-S6 kinase. Biochem. J. 305 (Pt 1), 25–28.
Hudson, C. C., Liu, M., Chiang, G. G., et al. (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol. Cell Biol. 22, 7004–7014.
Jacinto, E., Loewith, R., Schmidt, A., et al. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6, 1122–1128.
Sarbassov dos, D., Ali, S. M., Sengupta, S., et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168.
Bassell, G. J., Zhang, H., Byrd, A. L., et al. (1998) Sorting of beta-actin mRNA and protein to neurites and growth cones in culture. J. Neurosci. 18, 251–265.
Martin, K. C. (2004) Local protein synthesis during axon guidance and synaptic plasticity. Curr. Opin. Neurobiol. 14, 305–310.
Piper, M., Anderson, R., Dwivedy, A., et al. (2006) Signaling mechanisms underlying Slit2-induced collapse of Xenopus retinal growth cones. Neuron 49, 215–228.
Piper, M., and Holt, C. (2004) RNA translation in axons. Annu. Rev. Cell Dev. Biol. 20, 505–523.
Campbell, D. S., and Holt, C. E. (2001) Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32, 1013–1026.
Abe, H., Obinata, T., Minamide, L. S., and Bamburg, J. R. (1996) Xenopus laevis actin-depolymerizing factor/cofilin: a phosphorylation-regulated protein essential for development. J. Cell Biol. 132, 871–885.
Willis, D. E., and Twiss, J. L. (2006) The evolving roles of axonally synthesized proteins in regeneration. Curr. Opin. Neurobiol. 16, 111–118.
Verma, P., Chierzi, S., Codd, A. M., et al. (2005) Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration. J. Neurosci. 25, 331–342.
Selzer, M. E. (2003) Promotion of axonal regeneration in the injured CNS. Lancet Neurol. 2, 157–166.
Chuckowree, J. A., Dickson, T. C., and Vickers, J. C. (2004) Intrinsic regenerative ability of mature CNS neurons. Neuroscientist 10, 280–285.
Wessells, N. K., Johnson, S. R., and Nuttall, R. P. (1978) Axon initiation and growth cone regeneration in cultured motor neurons. Exp. Cell Res. 117, 335–345.
Blackmore, M., and Letourneau, P. C. (2006) Changes within maturing neurons limit axonal regeneration in the developing spinal cord. J. Neurobiol. 66, 348–360.
Sahly, I., Khoutorsky, A., Erez, H., Prager-Khoutorsky, M., and Spira, M. E. (2006) Online confocal imaging of the events leading to structural dedifferentiation of an axonal segment into a growth cone after axotomy. J. Comp. Neurol. 494, 705–720.
Jan, Y. N., and Jan, L. Y. (2003) The control of dendrite development. Neuron 40, 229–242.
McAllister, A. K. (2000) Cellular and molecular mechanisms of dendrite growth. Cereb. Cortex 10, 963–973.
Wong, R. O., and Ghosh, A. (2002) Activity-dependent regulation of dendritic growth and patterning. Nat. Rev. Neurosci. 3, 803–812.
Miller, F. D., and Kaplan, D. R. (2003) Signaling mechanisms underlying dendrite formation. Curr. Opin. Neurobiol. 13, 391–398.
Wirth, M. J., Brun, A., Grabert, J., Patz, S., and Wahle, P. (2003) Accelerated dendritic development of rat cortical pyramidal cells and interneurons after biolistic transfection with BDNF and NT4/5. Development 130, 5827–5838.
Whitford, K. L., Marillat, V., Stein, E., Goodman, C. S., Tessier-Lavigne, M., Chedotal, A., and Ghosh, A. (2002) Regulation of cortical dendrite development by Slit-Robo interactions. Neuron 33, 47–61.
Polleux, F., Morrow, T., and Ghosh, A. (2000) Semaphorin 3A is a chemoattractant for cortical apical dendrites. Nature 404, 567–573.
Horch, H. W., and Katz, L. C. (2002) BDNF release from single cells elicits local dendritic growth in nearby neurons. Nat. Neurosci. 5, 1177–1184.
Yu, X., and Malenka, R. C. (2003) Beta-catenin is critical for dendritic morphogenesis. Nat. Neurosci. 6, 1169–1177.
Redmond, L., Oh, S. R., Hicks, C., Weinmaster, G., and Ghosh, A. (2000) Nuclear Notch1 signaling and the regulation of dendritic development. Nat. Neurosci. 3, 30–40.
Lohmann, C., Myhr, K. L., and Wong, R. O. (2002) Transmitter-evoked local calcium release stabilizes developing dendrites. Nature 418, 177–181.
Bjorkblom, B., Ostman, N., Hongisto, V., et al. (2005) Constitutively active cytoplasmic c-Jun N-terminal kinase 1 is a dominant regulator of dendritic architecture: role of microtubule-associated protein 2 as an effector. J. Neurosci. 25, 6350–6361.
Wayman, G. A., Impey, S., Marks, D., et al. (2006) Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron 50, 897–909.
Nakayama, A. Y., Harms, M. B., and Luo, L. (2000) Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons. J. Neurosci. 20, 5329–5338.
Hayashi, K., Ohshima, T., and Mikoshiba, K. (2002) Pak1 is involved in dendrite initiation as a downstream effector of Rac1 in cortical neurons. Mol. Cell Neurosci. 20, 579–594.
Sholl, D. A. (1953) Dendritic organization in the neurons of the visual and motor cortices of the cat. J. Anat. 87, 387–406.
Kwon, C. H., Luikart, B. W., Powell, C. M., et al. (2006) Pten regulates neuronal arborization and social interaction in mice. Neuron 50, 377–388.
Dijkhuizen, P. A., and Ghosh, A. (2005) BDNF regulates primary dendrite formation in cortical neurons via the PI3-kinase and MAP kinase signaling pathways. J. Neurobiol. 62, 278–288.
Hering, H., and Sheng, M. (2001) Dendritic spines: structure, dynamics and regulation. Nat. Rev. Neurosci. 2, 880–888.
Yuste, R., and Bonhoeffer, T. (2004) Genesis of dendritic spines: insights from ultrastructrual and imaging studies. Nat. Rev. Neurosci. 5, 24–34.
Tada, T., and Sheng, M. (2006) Molecular mechanisms of dendritic spine morphogenesis. Curr. Opin. Neurobiol. 16, 95–101.
Casadio, A., Martin, K. C., Giustetto, M., et al. (1999) A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99, 221–237.
Tavazoie, S. F., Alvarez, V. A., Ridenour, D. A., Kwiatkowski, D. J., and Sabatini, B. L. (2005) Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat. Neurosci. 8, 1727–1734.
Kelleher, R. J., 3rd, Govindarajan, A., and Tonegawa, S. (2004) Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44, 59–73.
Squire, L. R., and Davis, H. P. (1981) The pharmacology of memory: a neurobiological perspective. Annu. Rev. Pharmacol. Toxicol. 21, 323–356.
Beaumont, V., Zhong, N., Fletcher, R., Froemke, R. C., and Zucker, R. S. (2001) Phosphorylation and local presynaptic protein synthesis in calcium- and calcineurin-dependent induction of crayfish long-term facilitation. Neuron 32, 489–501
Tang, S. J., Reis, G., Kang, H., Gingras, A. C., Sonenberg, N., and Schuman, E. M. (2002) A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc. natl. Acad. Sci. USA 99, 467–472.
Vickers, C. A., Dickson, K. S., and Wyllie, D. J. (2005) Induction and maintenance of latephase long-term potentiation in isolated dendrites of rat hippocampal CA1 pyramidal neurones. J. Physiol. 568, 803–813.
Cracco, J. B., Serrano, P., Moskowitz, S. I., Bergold, P. J., and Sacktor, T. C. (2005) Protein synthesis-dependent LTP in isolated dendrites of CA1 pyramidal cells. Hippocampus 15, 551–556.
Wang, Y., Barbaro, M. F., and Baraban, S. C. (2006) A role for the mTOR pathway in surface expression of AMPA receptors. Neurosci. Lett. 401, 35–39.
Job, C., and Eberwine, J. (2001) Identification of sites for exponential translation in living dendrites. Proc. Natl. Acad. Sci. USA 98, 13037–13042.
Huber, K. M., Roder, J. C., and Bear, M. F. (2001) Chemical induction of mGluR5- and protein synthesis-dependent long-term depression in hippocampal area CA1. J. Neurophysiol. 86, 321–325.
Banko, J. L., Hou, L., Poulin, F., Sonenberg, N., and Klann, E. (2006) Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor-dependent long-term depression. J. Neurosci. 26, 2167–2173.
Banko, J. L., Poulin, F., Hou, L., DeMaria, C. T., Sonenberg, N., and Klann, E. (2005) The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J. Neurosci. 25, 9581–9590.
Zho, W. M., You, J. L., Huang, C. C., and Hsu, K. S. (2002) The group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine induces a novel form of depotentiation in the CA1 region of the hippocampus. J. Neurosci. 22, 8838–8849.
Malenka, R. C. (1994) Synaptic plasticity in the hippocampus: LTP and LTD. Cell 78, 535–538.
Tischmeyer, W., Schicknick, H., Kraus, M., et al. (2003) Rapamycin-sensitive signalling in longterm consolidation of auditory cortex-dependent memory. Eur. J. Neurosci. 18, 942–950.
Lee, C. C., Huang, C. C., Wu, M. Y., and Hsu, K. S. (2005) Insulin stimulates postsynaptic density-95 protein translation via the phospho-inositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway. J. Biol. Chem. 280, 18543–18550.
Takei, N., Inamura, N., Kawamura, M., 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.
Kraut, R., Menon, K., and Zinn, K. (2001) A gain-of-function screen for genes controlling motor axon guidance and synaptogenesis in Drosophila. Curr. Biol. 11, 417–430.
Schratt, G. M., Nigh, E. A., Chen, W. G., Hu, L., and Greenberg, M. E. (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, 7366–7377.
Schratt, G. M., Tuebing, F., Nigh, E. A., et al. (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439, 283–289.
Yang, N., Higuchi, O., Ohashi, K., et al. (1998) Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature 393, 809–812.
Meng, Y., Zhang, Y., Tregoubov, V., et al. (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35, 121–133.
Zhou, Q., Homma, K. J., and Poo, M. M. (2004) Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44, 749–757.
Guzowski, J. F., Lyford, G. L., Stevenson, G. D., et al. (2000) Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J. Neurosci. 20, 3993–4001.
Vazquez, L. E., Chen, H. J., Sokolova, I., Knuesel, I., and Kennedy, M. B. (2004) SynGAP regulates spine formation. J. Neurosci. 24, 8862–8872.
Akama, K. T., and McEwen, B. S. (2003) Estrogen stimulates postsynaptic density-95 rapid protein synthesis via the Akt/protein kinase B pathway. J. Neurosci. 23, 2333–2339.
El-Husseini, A. E., Schnell, E., Chetkovich, D. M., Nicoll, R. A., and Bredt, D. S. (2000) PSD-95 involvement in maturation of excitatory synapses. Science 290, 1364–1368.
Fagiolini, M., Katagiri, H., Miyamoto, H., et al. (2003) Separable features of visual cortical plasticity revealed by N-methyl-D-aspartate receptor 2A signaling. Proc. Natl. Acad. Sci. USA 100, 2854–2859.
Yao, W. D., Gainetdinov, R. R., Arbuckle, M. I., et al. (2004) Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron 41, 625–638.
Onda, H., Crino, P. B., Zhang, H., et al. (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, 561–574.
Passafaro, M., Nakagawa, T., Sala, C., and Sheng, M. (2003) Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2. Nature 424, 677–681.
Liu, L., Wong, T. P., Pozza, M. F., et al. (2004) Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304, 1021–1024.
Kim, M. J., Dunah, A. W., Wang, Y. T., and Sheng, M. (2005) Differential roles of NR2A-and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron 46, 745–760.
Dent, E. W., and Gertler, F. B. (2003) Cytoskeletal dynamics and transport in growth cone motility and axon guidance. Neuron 40, 209–227.
Luo, L. (2002) Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. Annu. Rev. Cell Dev. Biol. 18, 601–635.
Matus, A. (2000) Actin-based plasticity in dendritic spines. Science 290, 754–758.
Khurana, V., Lu, Y., Steinhilb, M. L., Oldham, S., Shulman, J. M., and Feany, M. B. (2006) TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr. Biol. 16, 230–241.
Ravikumar, B., Vacher, C., Berger, Z., 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.
Kwiatkowski, D. J. (2003) Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. Cancer Biol. Ther. 2, 471–476.
Jozwiak, J., and Jozwiak, S. (2005) Giant cells: contradiction to two-hit model of tuber formation? Cell Mol. Neurobiol. 25, 795–805.
Kwiatkowski, D. J. (2003) Tuberous sclerosis: from tubers to mTOR. Ann. Hum. Genet. 67, 87–96.
Inoki, K., Corradetti, M. N., and Guan, K. L. (2005) Dysregulation of the TSC-mTOR pathway in human disease. Nat. Genet. 37, 19–24.
Johannessen, C. M., Reczek, E. E., James, M. F., Brems, H., Legius, E., and Cichowski, K. (2005) The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl. Acad. Sci. USA 102, 8573–8578.
Antar L. N., and Bassell, G. J. (2003) Sunrise at the synapse: the FMRP mRNP shaping the synaptic interface. Neuron 37, 555–558.
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Jaworski, J., Sheng, M. The growing role of mTOR in neuronal development and plasticity. Mol Neurobiol 34, 205–219 (2006). https://doi.org/10.1385/MN:34:3:205
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DOI: https://doi.org/10.1385/MN:34:3:205