Activity-dependent changes in the strength of synaptic connections are fundamental to the formation and maintenance of memory. The mechanisms underlying persistent changes in synaptic strength in the hippocampus, specifically long-term potentiation and depression, depend on new protein synthesis. Such changes are thought to be orchestrated by engaging the signaling pathways that regulate mRNA translation in neurons. In this review, we discuss the key regulatory pathways that govern translational control in response to synaptic activity and the mRNA populations that are specifically targeted by these pathways. The critical contribution of regulatory control over new protein synthesis to proper cognitive function is underscored by human disorders associated with either silencing or mutation of genes encoding proteins that directly regulate translation. In light of these clinical implications, we also consider the therapeutic potential of targeting dysregulated translational control to treat cognitive disorders of synaptic dysfunction.


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Literature Cited

  1. Alarcon JM, Hodgman R, Theis M, Huang Y-S, Kandel ER, Richter JD. 2004. Selective modulation of some forms of Schaffer Collateral-CA1 synaptic plasticity in mice with a disruption of the CPEB-1 gene. Learn. Mem. 11:318–27 [Google Scholar]
  2. Antion MD, Hou L, Wong H, Hoeffer CA, Klann E. 2008. 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 [Google Scholar]
  3. Auerbach BD, Osterweil EK, Bear MF. 2011. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480:63–68 [Google Scholar]
  4. Bagni C, Tassone F, Neri G, Hagerman R. 2012. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J. Clin. Investig. 122:4314–22 [Google Scholar]
  5. Banko JL, Merhav M, Stern E, Sonenberg N, Rosenblum K, Klann E. 2007. Behavioral alterations in mice lacking the translation repressor 4E-BP2. Neurobiol. Learn. Mem. 87:248–56 [Google Scholar]
  6. Banko JL, Poulin F, Hou L, DeMaria CT, Sonenberg N, Klann E. 2005. The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J. Neurosci. 25:9581–90 [Google Scholar]
  7. Barak S, Liu F, Hamida SB, Yowell QV, Neasta J. et al. 2013. Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse. Nat. Neurosci. 16:1111–17 [Google Scholar]
  8. Bassell GJ, Warren ST. 2008. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60:201–14 [Google Scholar]
  9. Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, Sabatini BL. 2013. Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron 78:510–22 [Google Scholar]
  10. Bateup HS, Takasaki KT, Saulnier JL, Denefrio CL, Sabatini BL. 2011. Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J. Neurosci. 31:8862–69 [Google Scholar]
  11. Bekinschtein P, Cammarota M, Igaz LM, Bevilaqua LR, Izquierdo I, Medina JH. 2007. Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus. Neuron 53:261–77 [Google Scholar]
  12. Belelovsky K, Elkobi A, Kaphzan H, Nairn AC, Rosenblum K. 2005. A molecular switch for translational control in taste memory consolidation. Eur. J. Neurosci. 22:2560–68 [Google Scholar]
  13. Berger-Sweeney J, Zearfoss NR, Richter JD. 2006. Reduced extinction of hippocampal-dependent memories in CPEB knockout mice. Learn. Mem. 13:4–7 [Google Scholar]
  14. Berlanga JJ, Ventoso I, Harding HP, Deng J, Ron D. et al. 2006. Antiviral effect of the mammalian translation initiation factor 2α kinase GCN2 against RNA viruses. EMBO J. 25:1730–40 [Google Scholar]
  15. Bhakar AL, Dölen G, Bear MF. 2012. The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35:417–43 [Google Scholar]
  16. Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC, Murphy JP, Pierre P, Klann E. 2012. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 76:325–37 [Google Scholar]
  17. Bidinosti M, Ran I, Sanchez-Carbente MR, Martineau Y, Gingras AC. et al. 2010. Postnatal deamidation of 4E-BP2 in brain enhances its association with raptor and alters kinetics of excitatory synaptic transmission. Mol. Cell 37:797–808 [Google Scholar]
  18. Bliss TV, Lømo T. 1973. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232:381–89 [Google Scholar]
  19. Blundell J, Kouser M, Powell CM. 2008. Systemic inhibition of mammalian target of rapamycin inhibits fear memory reconsolidation. Neurobiol. Learn. Mem. 90:28–35 [Google Scholar]
  20. Bolduc FV, Bell K, Cox H, Broadie KS, Tully T. 2008. Excess protein synthesis in Drosophila Fragile X mutants impairs long-term memory. Nat. Neurosci. 11:1143–45 [Google Scholar]
  21. Busquets-Garcia A, Gomis-González M, Guegan T, Agustín-Pavón C, Pastor A. et al. 2013. Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat. Med. 19:603–7 [Google Scholar]
  22. Cajigas IJ, Tushev G, Will TJ, Tom Dieck S, Fuerst N, Schuman EM. 2012. The local transcriptome in the synaptic neuropil revealed by deep sequencing and high-resolution imaging. Neuron 74:453–66 [Google Scholar]
  23. Cammalleri M, Lütjens R, Berton F, King AR, Simpson C. 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 100:14368–73 [Google Scholar]
  24. Cao R, Robinson B, Xu H, Gkogkas C, Khoutorsky A. et al. 2013. Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling. Neuron 79:712–24 [Google Scholar]
  25. Casadio A, Martin KC, Giustetto M, Zhu H, Chen 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 99:221–37 [Google Scholar]
  26. Chang RC, Suen KC, Ma CH, Elyaman W, Ng HK, Hugon J. 2002a. Involvement of double-stranded RNA-dependent protein kinase and phosphorylation of eukaryotic initiation factor-2alpha in neuronal degeneration. J. Neurochem. 83:1215–25 [Google Scholar]
  27. Chang RC, Wong AK, Ng HK, Hugon J. 2002b. Phosphorylation of eukaryotic initiation factor-2α (eIF2α) is associated with neuronal degeneration in Alzheimer's disease. Neuroreport 13:2429–32 [Google Scholar]
  28. Chen A, Muzzio IA, Malleret G, Bartsch D, Verbitsky M. et al. 2003. Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron 39:655–69 [Google Scholar]
  29. Costa-Mattioli M, Gobert D, Harding H, Herdy B, Azzi M. et al. 2005. Translational control of hippocampal synaptic plasticity and memory by the eIF2α kinase, GCN2. Nature 436:1166–73 [Google Scholar]
  30. Costa-Mattioli M, Gobert D, Stern E, Gamache K, Colina R. et al. 2007. eIF2α phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 129:195–206 [Google Scholar]
  31. Costa-Mattioli M, Monteggia LM. 2013. mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat. Neurosci. 16:1537–43 [Google Scholar]
  32. Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N. 2009. Translational control of long-lasting synaptic plasticity and memory. Neuron 61:10–26 [Google Scholar]
  33. Couturier J, Morel M, Pontcharraud R, Gontier V, Fauconneau B. et al. 2010. Interaction of double-stranded RNA-dependent protein kinase (PKR) with the death receptor signaling pathway in amyloid β (Aβ)-treated cells and in APPSLPS1 knock-in mice. J. Biol. Chem. 285:1272–82 [Google Scholar]
  34. Couturier J, Paccalin M, Morel M, Terro F, Milin S. et al. 2011. Prevention of the β-amyloid peptide-induced inflammatory process by inhibition of double-stranded RNA-dependent protein kinase in primary murine mixed co-cultures. J. Neuroinflammation 8:72 [Google Scholar]
  35. Darnell JC, Klann E. 2013. The translation of translational control by FMRP: therapeutic targets for FXS. Nat. Neurosci. 16:1530–36 [Google Scholar]
  36. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A. et al. 2011. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247–61 [Google Scholar]
  37. Davidkova G, Carroll RC. 2007. Characterization of the role of microtubule-associated protein 1B in metabotropic glutamate receptor-mediated endocytosis of AMPA receptors in hippocampus. J. Neurosci. 27:13273–78 [Google Scholar]
  38. De Rubeis S, Pasciuto E, Li KW, Fernández E, Di Marino D. et al. 2013. CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron 79:1169–82 [Google Scholar]
  39. Dever TE, Green R. 2012. The elongation, termination, and recycling phases of translation in eukaryotes. Cold Spring Harb. Perspect. Biol. 4:a013706 [Google Scholar]
  40. Devi CR, Ohno M. 2013. Deletion of the eIF2α kinase GCN2 fails to rescue the memory decline associated with Alzheimer's disease. PLoS ONE 8:e77335 [Google Scholar]
  41. Dolan BM, Duron SG, Campbell DA, Vollrath B, Shankaranarayana Rao BS. et al. 2013. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486. Proc. Natl. Acad. Sci. USA 110:5671–76 [Google Scholar]
  42. Doyle JP, Dougherty JD, Heiman M, Schmidt EF, Stevens TR. et al. 2008. Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135:749–62 [Google Scholar]
  43. Dudai Y. 2012. The restless engram: consolidations never end. Annu. Rev. Neurosci. 35:227–47 [Google Scholar]
  44. Dyer JR, Michel S, Lee W, Castellucci VF, Wayne NL, Sossin WS. 2003. An activity-dependent switch to cap-independent translation triggered by eIF4E dephosphorylation. Nat. Neurosci. 6:219–20 [Google Scholar]
  45. Eberwine J, Belt B, Kacharmina JE, Miyashiro K. 2002. Analysis of subcellularly localized mRNAs using in situ hybridization, mRNA amplification, and expression profiling. Neurochem. Res. 27:1065–77 [Google Scholar]
  46. Ehninger D, Han S, Shilyansky C, Zhou Y, Li W. et al. 2008. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat. Med. 14:843–48 [Google Scholar]
  47. Ehninger D, Silva AJ. 2011. Rapamycin for treating tuberous sclerosis and autism spectrum disorders. Trends Mol. Med. 17:78–87 [Google Scholar]
  48. Endersby R, Baker SJ. 2008. PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene 27:5416–30 [Google Scholar]
  49. Fombonne E. 1999. The epidemiology of autism: a review. Psychol. Med. 29:769–86 [Google Scholar]
  50. Frey U, Morris RG. 1997. Synaptic tagging and long-term potentiation. Nature 385:533–36 [Google Scholar]
  51. García MA, Meurs EF, Esteban M. 2007. The dsRNA protein kinase PKR: virus and cell control. Biochimie 89:799–811 [Google Scholar]
  52. Gildish I, Manor D, David O, Sharma V, Williams D. et al. 2012. Impaired associative taste learning and abnormal brain activation in kinase-defective eEF2K mice. Learn. Mem. 19:116–25 [Google Scholar]
  53. Gingras AC, Raught B, Sonenberg N. 2004. mTOR signaling to translation. Curr. Top. Microbiol. Immunol. 279:169–97 [Google Scholar]
  54. Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T. et al. 2013. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493:371–77 [Google Scholar]
  55. Goorden SM, van Woerden GM, van der Weerd L, Cheadle JP, Elgersma Y. 2007. Cognitive deficits in Tsc1+/− mice in the absence of cerebral lesions and seizures. Ann. Neurol. 62:648–55 [Google Scholar]
  56. Govindarajan A, Israely I, Huang S-Y, Tonegawa S. 2011. The dendritic branch is the preferred integrative unit for protein synthesis-dependent LTP. Neuron 69:132–46 [Google Scholar]
  57. Hay N, Sonenberg N. 2004. Upstream and downstream of mTOR. Genes Dev. 18:1926–45 [Google Scholar]
  58. Hayashi ML, Choi SY, Rao BS, Jung HY, Lee HK. et al. 2004. Altered cortical synaptic morphology and impaired memory consolidation in forebrain-specific dominant-negative PAK transgenic mice. Neuron 42:773–87 [Google Scholar]
  59. Henry FE, McCartney AJ, Neely R, Perez AS, Carruthers CJ. et al. 2012. Retrograde changes in presynaptic function driven by dendritic mTORC1. J. Neurosci. 32:17128–42 [Google Scholar]
  60. Hinnebusch AG. 2005. Translational regulation of GCN4 and the general amino acid control of yeast. Annu. Rev. Microbiol. 59:407–50 [Google Scholar]
  61. Hoeffer CA, Cowansage KK, Arnold EC, Banko JL, Moerke NJ. et al. 2011. Inhibition of the interactions between eukaryotic initiation factors 4E and 4G impairs long-term associative memory consolidation but not reconsolidation. Proc. Natl. Acad. Sci. USA 108:3383–88 [Google Scholar]
  62. Hoeffer CA, Sanchez E, Hagerman RJ, Mu Y, Nguyen DV. et al. 2012. Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav. 11:332–41 [Google Scholar]
  63. Hoeffer CA, Santini E, Ma T, Arnold EC, Whelan AM. et al. 2013. Multiple components of eIF4F are required for protein synthesis-dependent hippocampal long-term potentiation. J. Neurophysiol. 109:68–76 [Google Scholar]
  64. Hou L, 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. 24:6352–61 [Google Scholar]
  65. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR. et al. 2012. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485:55–61 [Google Scholar]
  66. Huang F, Chotiner JK, Steward O. 2005. The mRNA for elongation factor 1α is localized in dendrites and translated in response to treatments that induce long-term depression. J. Neurosci. 25:7199–209 [Google Scholar]
  67. Huang W, Zhu PJ, Zhang S, Zhou H, Stoica L. et al. 2013. mTORC2 controls actin polymerization required for consolidation of memory. Nat. Neurosci. 16:441–48 [Google Scholar]
  68. Huang YS, Jung MY, Sarkissian M, Richter JD. 2002. N-methyl-d-aspartate receptor signaling results in Aurora kinase-catalyzed CPEB phosphorylation and alpha CaMKII mRNA polyadenylation at synapses. EMBO J. 21:2139–48 [Google Scholar]
  69. Huang YS, Kan MC, Lin CL, Richter JD. 2006. CPEB3 and CPEB4 in neurons: analysis of RNA-binding specificity and translational control of AMPA receptor GluR2 mRNA. EMBO J. 25:4865–76 [Google Scholar]
  70. Huber KM, Kayser MS, Bear MF. 2000. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288:1254–57 [Google Scholar]
  71. Ingolia NT, Ghaemmaghami S, Newman JRS, Weissman JS. 2009. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324:218–23 [Google Scholar]
  72. Jackson RJ, Hellen CU, Pestova TV. 2010. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat. Rev. Mol. Cell Biol. 11:113–27 [Google Scholar]
  73. Jackson RJ, Hellen CU, Pestova TV. 2012. Termination and post-termination events in eukaryotic translation. Adv. Protein Chem. Struct. Biol. 86:45–93 [Google Scholar]
  74. Jakawich SK, Nasser HB, Strong MJ, McCartney AJ, Perez AS. et al. 2010. Local presynaptic activity gates homeostatic changes in presynaptic function driven by dendritic BDNF synthesis. Neuron 68:1143–58 [Google Scholar]
  75. Jiang Z, Belforte JE, Lu Y, Yabe Y, Pickel J. et al. 2010. eIF2α phosphorylation-dependent translation in CA1 pyramidal cells impairs hippocampal memory consolidation without affecting general translation. J. Neurosci. 30:2582–94 [Google Scholar]
  76. Kandel ER. 2001. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294:1030–38 [Google Scholar]
  77. Kang H, Schuman EM. 1996. A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273:1402–6 [Google Scholar]
  78. Karim MM, Svitkin YV, Kahvejian A, De Crescenzo G, Costa-Mattioli M, Sonenberg N. 2006. A mechanism of translational repression by competition of Paip2 with eIF4G for poly(A) binding protein (PABP) binding. Proc. Natl. Acad. Sci. USA 103:9494–99 [Google Scholar]
  79. Khaleghpour K, Kahvejian A, De Crescenzo G, Roy G, Svitkin YV. et al. 2001. Dual interactions of the translational repressor Paip2 with poly(A) binding protein. Mol. Cell. Biol. 21:5200–13 [Google Scholar]
  80. Khandjian EW, Corbin F, Woerly S, Rousseau F. 1996. The fragile X mental retardation protein is associated with ribosomes. Nat. Genet. 12:91–93 [Google Scholar]
  81. Khoutorsky A, Yanagiya A, Gkogkas CG, Fabian MR, Prager-Khoutorsky M. et al. 2013. Control of synaptic plasticity and memory via suppression of poly(A)-binding protein. Neuron 78:298–311 [Google Scholar]
  82. Krüttner S, Stepien B, Noordermeer JN, Mommaas MA, Mechtler K. et al. 2012. Drosophila CPEB Orb2A mediates memory independent of its RNA-binding domain. Neuron 76:383–95 [Google Scholar]
  83. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA. et al. 2006. Pten regulates neuronal arborization and social interaction in mice. Neuron 50:377–88 [Google Scholar]
  84. Laggerbauer B, Ostareck D, Keidel EM, Ostareck-Lederer A, Fischer U. 2001. Evidence that fragile X mental retardation protein is a negative regulator of translation. Hum. Mol. Genet. 10:329–38 [Google Scholar]
  85. Langstrom NS, Anderson JP, Lindroos HG, Winblad B, Wallace WC. 1989. Alzheimer's disease-associated reduction of polysomal mRNA translation. Brain Res. Mol. Brain Res. 5:259–69 [Google Scholar]
  86. Laplante M, Sabatini DM. 2012. mTOR signaling in growth control and disease. Cell 149:274–93 [Google Scholar]
  87. Laurenco MV, Clarke JR, Frozza RL, Bomfim TR, Forny-Germano L. et al. 2013. TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys. Cell Metab. 18:831–43 [Google Scholar]
  88. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A. et al. 2007. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–76 [Google Scholar]
  89. Li Z, Zhang Y, Ku L, Wilkinson KD, Warren ST, Feng Y. 2001. The fragile X mental retardation protein inhibits translation via interacting with mRNA. Nucleic Acids Res. 29:2276–83 [Google Scholar]
  90. Lu PD, Harding HP, Ron D. 2004. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J. Cell Biol. 167:27–33 [Google Scholar]
  91. Lüscher C, Huber KM. 2010. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65:445–59 [Google Scholar]
  92. Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E. et al. 2013. Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits. Nat. Neurosci. 16:1299–305 [Google Scholar]
  93. Ma XM, Blenis J. 2009. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 10:307–18 [Google Scholar]
  94. Majumdar A, Cesario WC, White-Grindley E, Jiang H, Ren F. et al. 2012. Critical role of amyloid-like oligomers of Drosophila Orb2 in the persistence of memory. Cell 148:515–29 [Google Scholar]
  95. Malenka RC, Bear MF. 2004. LTP and LTD: an embarrassment of riches. Neuron 44:5–21 [Google Scholar]
  96. Martin KC, Casadio A, Zhu H, Yaping E, Rose JC. et al. 1997. Synapse-specific, long-term facilitation of Aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91:927–38 [Google Scholar]
  97. Martin KC, Ephrussi A. 2009. mRNA localization: gene expression in the spatial dimension. Cell 136:719–30 [Google Scholar]
  98. McGaugh JL. 2000. Memory–a century of consolidation. Science 287:248–51 [Google Scholar]
  99. Mefford HC, Batshaw ML, Hoffman EP. 2012. Genomics, intellectual disability, and autism. N. Engl. J. Med. 366:733–43 [Google Scholar]
  100. Milekic MH, Alberini CM. 2002. Temporally graded requirement for protein synthesis following memory reactivation. Neuron 36:521–25 [Google Scholar]
  101. Miniaci MC, Kim JH, Puthanveettil SV, Si K, Zhu H. et al. 2008. Sustained CPEB-dependent local protein synthesis is required to stabilize synaptic growth for persistence of long-term facilitation in Aplysia. Neuron 59:1024–36 [Google Scholar]
  102. Morel M, Couturier J, Lafay-Chebassier C, Paccalin M, Page G. 2009. PKR, the double stranded RNA-dependent protein kinase as a critical target in Alzheimer's disease. J. Cell. Mol. Med. 13:1476–88 [Google Scholar]
  103. Muddashetty RS, Kelić S, Gross C, Xu M, Bassell GJ. 2007. Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome. J. Neurosci. 27:5338–48 [Google Scholar]
  104. Nader K, Schafe GE, Le Doux JE. 2000. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722–26 [Google Scholar]
  105. Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F. et al. 2008. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134:1042–54 [Google Scholar]
  106. Nelson DL, Orr HT, Warren ST. 2013. The unstable repeats—three evolving faces of neurological disease. Neuron 77:825–43 [Google Scholar]
  107. Neves G, Cooke SF, Bliss TV. 2008. Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat. Rev. Neurosci. 9:65–75 [Google Scholar]
  108. O'Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J. et al. 2008. Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis. Neuron 60:988–1009 [Google Scholar]
  109. O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB. et al. 2012. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338:1619–22 [Google Scholar]
  110. Onuki R, Bando Y, Suyama E, Katayama T, Kawasaki H. et al. 2004. An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer's disease. EMBO J. 23:959–68 [Google Scholar]
  111. Page G, Rioux Bilan A, Ingrand S, Lafay-Chebassier C, Pain S. et al. 2006. Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer's disease. Neuroscience 139:1343–54 [Google Scholar]
  112. Park S, Park JM, Kim S, Kim JA, Shepherd JD. et al. 2008. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 59:70–83 [Google Scholar]
  113. Pavitt GD, Ramaiah KV, Kimball SR, Hinnebusch AG. 1998. eIF2 independently binds two distinct eIF2B subcomplexes that catalyze and regulate guanine-nucleotide exchange. Genes Dev. 12:514–26 [Google Scholar]
  114. Penney J, Tsurudome K, Liao EH, Elazzouzi F, Livingstone M. et al. 2012. TOR is required for the retrograde regulation of synaptic homeostasis at the Drosophila neuromuscular junction. Neuron 74:166–78 [Google Scholar]
  115. Poon MM, Choi SH, Jamieson CA, Geschwind DH, Martin KC. 2006. Identification of process-localized mRNAs from cultured rodent hippocampal neurons. J. Neurosci. 26:13390–99 [Google Scholar]
  116. Qin M, Kang J, Burlin TV, Jiang C, Smith CB. 2005. Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the FMR1 null mouse. J. Neurosci. 25:5087–95 [Google Scholar]
  117. Ran I, Gkogkas CG, Vasuta C, Tartas M, Khoutorsky A. et al. 2013. Selective regulation of GluA subunit synthesis and AMPA receptor-mediated synaptic function and plasticity by the translation repressor 4E-BP2 in hippocampal pyramidal cells. J. Neurosci. 33:1872–86 [Google Scholar]
  118. Redondo RL, Morris RGM. 2011. Making memories last: the synaptic tagging and capture hypothesis. Nat. Rev. Neurosci. 12:17–30 [Google Scholar]
  119. Richter JD, Klann E. 2009. Making synaptic plasticity and memory last: mechanisms of translational regulation. Genes Dev. 23:1–11 [Google Scholar]
  120. Ron D, Harding HP. 2007. eIF2α phosphorylation in cellular stress responses and disease. Translational Control in Biology and Medicine MB Mathews, N Sonenberg, JWB Hershey 345–68 Cold Spring Harbor, NY: Cold Spring Harbor Lab. Press [Google Scholar]
  121. Ruvinsky I, Sharon N, Lerer T, Cohen H, Stolovich-Rain M. et al. 2005. Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev. 19:2199–211 [Google Scholar]
  122. Sahin M. 2012. Targeted treatment trials for tuberous sclerosis and autism: no longer a dream. Curr. Opin. Neurobiol. 22:895–901 [Google Scholar]
  123. Santini E, Huynh TN, MacAskill AF, Carter AG, Pierre P. et al. 2013. Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 493:411–15 [Google Scholar]
  124. Sharma A, Hoeffer CA, Takayasu Y, Miyawaki T, McBride SM. et al. 2010. Dysregulation of mTOR signaling in fragile X syndrome. J. Neurosci. 30:694–702 [Google Scholar]
  125. Shires KL, Da Silva BM, Hawthorne JP, Morris RG, Martin SJ. 2012. Synaptic tagging and capture in the living rat. Nat. Commun. 3:1246 [Google Scholar]
  126. Si K, Choi Y-B, White-Grindley E, Majumdar A, Kandel ER. 2010. Aplysia CPEB can form prion-like multimers in sensory neurons that contribute to long-term facilitation. Cell 140:421–35 [Google Scholar]
  127. Si K, Giustetto M, Etkin A, Hsu R, Janisiewicz AM. et al. 2003a. A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in Aplysia. Cell 115:893–904 [Google Scholar]
  128. Si K, Lindquist S, Kandel ER. 2003b. A neuronal isoform of the Aplysia CPEB has prion-like properties. Cell 115:879–91 [Google Scholar]
  129. Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR. et al. 2013. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2:e00498 [Google Scholar]
  130. Silva AJ, Paylor R, Wehner JM, Tonegawa S. 1992a. Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science 257:206–11 [Google Scholar]
  131. Silva AJ, Stevens CF, Tonegawa S, Wang Y. 1992b. Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science 257:201–6 [Google Scholar]
  132. Sonenberg N, Hinnebusch AG. 2009. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136:731–45 [Google Scholar]
  133. Stefani G, Fraser CE, Darnell JC, Darnell RB. 2004. Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells. J. Neurosci. 24:7272–76 [Google Scholar]
  134. Stern E, Chinnakkaruppan A, David O, Sonenberg N, Rosenblum K. 2013. Blocking the eIF2α kinase (PKR) enhances positive and negative forms of cortex-dependent taste memory. J. Neurosci. 33:2517–25 [Google Scholar]
  135. Steward O. 1997. mRNA localization in neurons: a multipurpose mechanism?. Neuron 18:9–12 [Google Scholar]
  136. Steward O, Levy WB. 1982. Preferential localization of polyribosomes under the base of dendritic spines in granule cells of the dentate gyrus. J. Neurosci. 2:284–91 [Google Scholar]
  137. Steward O, Schuman EM. 2001. Protein synthesis at synaptic sites on dendrites. Annu. Rev. Neurosci. 24:299–325 [Google Scholar]
  138. Stoica L, Zhu PJ, Huang W, Zhou H, Kozma SC, Costa-Mattioli M. 2011. Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage. Proc. Natl. Acad. Sci. USA 108:3791–96 [Google Scholar]
  139. Sutton MA, Ito HT, Cressy P, Kempf C, Woo JC, Schuman EM. 2006. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis. Cell 125:785–99 [Google Scholar]
  140. Sutton MA, Schuman EM. 2006. Dendritic protein synthesis, synaptic plasticity, and memory. Cell 127:49–58 [Google Scholar]
  141. Sutton MA, Taylor AM, Ito HT, Pham A, Schuman EM. 2007. Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. Neuron 55:648–61 [Google Scholar]
  142. Sutton MA, Wall NR, Aakalu GN, Schuman EM. 2004. Regulation of dendritic protein synthesis by miniature synaptic events. Science 304:1979–83 [Google Scholar]
  143. Swanger SA, Bassell GJ. 2011. Making and breaking synapses through local mRNA regulation. Curr. Opin. Genet. Dev. 21:414–21 [Google Scholar]
  144. Taha E, Gildish I, Gal-Ben-Ari S, Rosenblum K. 2013. The role of eEF2 pathway in learning and synaptic plasticity. Neurobiol. Learn. Mem. 105:100–6 [Google Scholar]
  145. Takei N, Kawamura M, Hara K, Yonezawa K, Nawa H. 2001. Brain-derived neurotrophic factor enhances neuronal translation by activating multiple initiation processes: comparison with the effects of insulin. J. Biol. Chem. 276:42818–25 [Google Scholar]
  146. Takeuchi K, Gertner MJ, Zhou J, Parada LF, Bennett MV, Zukin RS. 2013. Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism. Proc. Natl. Acad. Sci. USA 110:4738–43 [Google Scholar]
  147. 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. USA 99:467–72 [Google Scholar]
  148. Thoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM. 2012. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485:109–13 [Google Scholar]
  149. Trinh MA, Kaphzan H, Wek RC, Pierre P, Cavener DR, Klann E. 2012. Brain-specific disruption of the eIF2α kinase PERK decreases ATF4 expression and impairs behavioral flexibility. Cell Rep. 1:676–88 [Google Scholar]
  150. Tsokas P, Grace EA, Chan P, Ma T, Sealfon SC. et al. 2005. Local protein synthesis mediates a rapid increase in dendritic elongation factor 1A after induction of late long-term potentiation. J. Neurosci. 25:5833–43 [Google Scholar]
  151. 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. 27:5885–94 [Google Scholar]
  152. Tsukiyama-Kohara K, Poulin F, Kohara M, DeMaria CT, Cheng A. et al. 2001. Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1. Nat. Med. 7:1128–32 [Google Scholar]
  153. Udagawa T, Farney NG, Jakovcevski M, Kaphzan H, Alarcon JM. et al. 2013. Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat. Med. 19:1473–77 [Google Scholar]
  154. Udagawa T, Swanger SA, Takeuchi K, Kim JH, Nalavadi V. et al. 2012. Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex. Mol. Cell 47:253–66 [Google Scholar]
  155. Vattem KM, Wek RC. 2004. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl. Acad. Sci. USA 101:11269–74 [Google Scholar]
  156. Viana Di Prisco G, Huang W, Buffington SA, Hsu C-C, Bonnen P. et al. 2014. Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α. Nat. Neurosci In press [Google Scholar]
  157. Wang DO, Martin KC, Zukin RS. 2010a. Spatially restricting gene expression by local translation at synapses. Trends Neurosci. 33:173–82 [Google Scholar]
  158. Wang X, Luo YX, He YY, Li FQ, Shi HS. et al. 2010b. Nucleus accumbens core mammalian target of rapamycin signaling pathway is critical for cue-induced reinstatement of cocaine seeking in rats. J. Neurosci. 30:12632–41 [Google Scholar]
  159. Weatherill DB, Dyer J, Sossin WS. 2010. Ribosomal protein S6 kinase is a critical downstream effector of the target of rapamycin complex 1 for long-term facilitation in Aplysia. J. Biol. Chem. 285:12255–67 [Google Scholar]
  160. Weatherill DB, McCamphill PK, Pethoukov E, Dunn TW, Fan X, Sossin WS. 2011. Compartment-specific, differential regulation of eukaryotic elongation factor 2 and its kinase within Aplysia sensory neurons. J. Neurochem. 117:841–55 [Google Scholar]
  161. Wu L, Wells D, Tay J, Mendis D, Abbott MA. et al. 1998. CPEB-mediated cytoplasmic polyadenylation and the regulation of experience-dependent translation of α-CaMKII mRNA at synapses. Neuron 21:1129–39 [Google Scholar]
  162. Wullschleger S, Loewith R, Hall MN. 2006. TOR signaling in growth and metabolism. Cell 124:471–84 [Google Scholar]
  163. Zhu PJ, Huang W, Kalikulov D, Yoo JW, Placzek AN. et al. 2011. Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition. Cell 147:1384–96 [Google Scholar]
  164. Zoghbi HY, Bear MF. 2012. Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 4:3a009886 [Google Scholar]

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