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The mTORC1 inhibitor rapamycin and the mTORC1/2 inhibitor AZD2014 impair the consolidation and persistence of contextual fear memory

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Abstract

Rationale

The mechanistic target of rapamycin (mTOR) kinase mediates various long-lasting forms of synaptic and behavioural plasticity. However, there is little information concerning the temporal pattern of mTOR activation and susceptibility to pharmacological intervention during consolidation of contextual fear memory. Moreover, the contribution of both mTOR complex 1 and 2 together or the mTOR complex 1 downstream effector p70S6K (S6K1) to consolidation of contextual fear memory is unknown.

Objective

Here, we tested whether different timepoints of vulnerability to rapamycin, a first generation mTOR complex 1 inhibitor, exist for contextual fear memory consolidation and persistence. We also sought to characterize the effects of dually inhibiting mTORC1/2 as well as S6K1 on fear memory formation and persistence.

Methods

Rapamycin was injected systemically to mice immediately, 3 h, or 12 h after contextual fear conditioning, and retention was measured at different timepoints thereafter. To determine the effects of a single injection of the dual mTROC1/2 inhibitor AZD2014 after learning on memory consolidation and persistence, a dose-response experiment was carried out. Memory formation and persistence was also assessed in response to the S6K1 inhibitor PF-4708671.

Results

A single systemic injection of rapamycin immediately or 3 h, but not 12 h, after learning impaired the formation and persistence of contextual fear memory. AZD2014 was found, with limitations, to dose-dependently attenuate memory consolidation and persistence at the highest dose tested (50 mg/kg). In contrast, PF-4708671 had no effect on consolidation or persistence.

Conclusion

Our results indicate the need to further understand the role of mTORC1/2 kinase activity in the molecular mechanisms underlying memory processing and also demonstrate that the effects of mTORC1 inhibition at different timepoints well after learning on memory consolidation and persistence.

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References

  • Abel T, Lattal KM (2001) Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr Opin Neurobiol 11(2):180–187

    CAS  PubMed  Google Scholar 

  • Angliker N, Ruegg MA (2013) In vivo evidence for mTORC2-mediated actin cytoskeleton rearrangement in neurons. Bioarchitecture 3(4):113–118

    PubMed  PubMed Central  Google Scholar 

  • Antion MD, Merhav M, Hoeffer CA, Reis G, Kozma SC, Thomas G, Schuman EM, Rosenblum K, Klann E (2008) Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity. Learning & Memory (Cold Spring Harbor, N.Y.), 15(1), 29–38

    Google Scholar 

  • Arriola Apelo SI, Lamming DW (2016) Rapamycin: an InhibiTOR of aging emerges from the soil of Easter Island. J Gerontol A Biol Sci Med Sci 71(7):841–849

    PubMed  PubMed Central  Google Scholar 

  • Arriola Apelo SI, Neuman JC, Baar EL, Syed FA, Cummings NE, Brar HK, Pumper CP, Kimple ME, Lamming DW (2016) Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell 15(1):28–38

    CAS  PubMed  Google Scholar 

  • Aslam N, Kubota Y, Wells D, Shouval HZ (2009) Translational switch for long-term maintenance of synaptic plasticity. Mol Syst Biol 5:284

    PubMed  PubMed Central  Google Scholar 

  • Babayan AH, Kramar EA, Barrett RM, Jafari M, Haettig J, Chen LY, Rex CS, Lauterborn JC, Wood MA, Gall CM, Lynch G (2012) Integrin dynamics produce a delayed stage of long-term potentiation and memory consolidation. J Neurosci 32(37):12854–12861

    CAS  PubMed  PubMed Central  Google Scholar 

  • Banko JL, Klann E (2008) Cap-dependent translation initiation and memory. Prog Brain Res 169:59–80

    CAS  PubMed  Google Scholar 

  • Basu B, Dean E, Puglisi M, Greystoke A, Ong M, Burke W, Cavallin M, Bigley G, Womack C, Harrington EA, Green S, Oelmann E, de Bono JS, Ranson M, Banerji U (2015) First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014. Clin Cancer Res 21(15):3412–3419

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bekinschtein P, Cammarota M, Igaz LM, Bevilaqua LR, Izquierdo I, Medina JH (2007a) Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus. Neuron 53(2):261–277

    CAS  PubMed  Google Scholar 

  • Bekinschtein P, Katche C, Slipczuk LN, Igaz LM, Cammarota M, Izquierdo I, Medina JH (2007b) mTOR signaling in the hippocampus is necessary for memory formation. Neurobiol Learn Mem 87(2):303–307

    CAS  PubMed  Google Scholar 

  • Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH (2008) BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A 105(7):2711–2716

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bekinschtein P, Katche C, Slipczuk L, Gonzalez C, Dorman G, Cammarota M, Izquierdo I, Medina JH (2010) Persistence of long-term memory storage: new insights into its molecular signatures in the hippocampus and related structures. Neurotox Res 18(3–4):377–385

    CAS  PubMed  Google Scholar 

  • Benavides-Serrato A, Lee J, Holmes B, Landon KA, Bashir T, Jung ME, Lichtenstein A, Gera J (2017) Specific blockade of rictor-mTOR association inhibits mTORC2 activity and is cytotoxic in glioblastoma. PLoS One 12(4):e0176599

    PubMed  PubMed Central  Google Scholar 

  • 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(2):325–337

    CAS  PubMed  PubMed Central  Google Scholar 

  • Blundell J, Kouser M, Powell CM (2008) Systemic inhibition of mammalian target of rapamycin inhibits fear memory reconsolidation. Neurobiol Learn Mem 90(1):28–35

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bottiger Y, Sawe J, Brattstrom C, Tollemar J, Burke JT, Hass G et al (2001) Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers. Clin Pharmacol Ther 69(1):32–40

    CAS  PubMed  Google Scholar 

  • Bourtchouladze R, Berman AN, Lapidus GK, Kandel ER (1998) Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learn Mem 5(4–5):365–374

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cai W, Blundell J, Han J, Greene RW, Powell CM (2006) Post-reactivation glucocorticoids impair recall of established fear memory. J Neurosci 26:9560–9566

    CAS  PubMed  PubMed Central  Google Scholar 

  • Choo AY, Yoon SO, Kim SG, Roux PP, Blenis J (2008) Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. PNAS 105(45):17414–17419

    CAS  PubMed  Google Scholar 

  • Curzon P, Rustay NR, Browman KE (2009) Cued and contextual fear conditioning for rodents. In: Buccafusco JJ (ed) Methods of behavior analysis in neuroscience, 2nd edn. Taylor & Francis Group, Boca Raton

    Google Scholar 

  • Dash PK, Orsi SA, Moore AN (2006) Spatial memory formation and memory-enhancing effect of glucose involves activation of the tuberous sclerosis complex-mammalian target of rapamycin pathway. J Neurosci 26(31):8048–8056

    CAS  PubMed  PubMed Central  Google Scholar 

  • Davis HP, Squire LR (1984) Protein synthesis and memory: a review. Psychol Bull 96(3):518–559

    CAS  PubMed  Google Scholar 

  • Desgranges B, Lévy F, Ferreira G (2008) Anisomycin infusion in amygdala impairs consolidation of odor aversion memory. Brain Res 1236:166–175. https://doi.org/10.1016/j.brainres.2008.07.123

    Article  CAS  PubMed  Google Scholar 

  • Drion CM, Borm LE, Kooijman L, Aronica E, Wadman WJ, Hartog AF, van Vliet EA, Gorter JA (2016) Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats. Epilepsia 57(5):688–697

    CAS  PubMed  Google Scholar 

  • Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D et al (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7(2):e38

    PubMed  Google Scholar 

  • Flexner LB, Flexner JB, Roberts RB (1967) Memory in mice analyzed with antibiotics. Antibiotics are useful to study stages of memory and to indicate molecular events which sustain memory. Science 155(3768):1377–1383

    CAS  PubMed  Google Scholar 

  • Freeman FM, Rose SP, Scholey AB (1995) Two time windows of Anisomycin-induced amnesia for passive avoidance training in the day-old chick. Neurobiol Learn Mem 63(3):291–295. https://doi.org/10.1006/nlme.1995.1034

    Article  CAS  PubMed  Google Scholar 

  • Gafford GM, Parsons RG, Helmstetter FJ (2011) Consolidation and reconsolidation of contextual fear memory requires mammalian target of rapamycin-dependent translation in the dorsal hippocampus. Neuroscience 182:98–104

    CAS  PubMed  PubMed Central  Google Scholar 

  • Glover EM, Ressler KJ, Davis M (2010) Differing effects of systemically administered rapamycin on consolidation and reconsolidation of context vs. cued fear memories. Learn Mem 17(11):577–581

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grechsch G, Matthies H (1980) Two sensitive periods for the amnesic effect of anisomycin. Pharmacology, Biochemistry, and Behavior, 12(5):663–5. https://doi.org/10.1016/0091-3057(80)90145-8

  • Guichard SM, Curwen J, Bihani T, D'Cruz CM, Yates JW, Grondine M et al (2015) AZD2014, an inhibitor of mTORC1 and mTORC2, is highly effective in ER+ breast cancer when administered using intermittent or continuous schedules. Mol Cancer Ther 14(11):2508–2518

    CAS  PubMed  Google Scholar 

  • Hernandez PJ, Abel T (2008) The role of protein synthesis in memory consolidation: progress amid decades of debate. Neurobiol Learn Mem 89(3):293–311

    CAS  PubMed  Google Scholar 

  • Hoeffer CA, Tang W, Wong H, Santillan A, Patterson RJ, Martinez LA, Tejada-Simon MV, Paylor R, Hamilton SL, Klann E (2008) Removal of FKBP12 enhances mTOR-raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron 60(5):832–845

    CAS  PubMed  PubMed Central  Google Scholar 

  • Honcharik N, Fryer J, Yatscoff R (1992) Pharmacokinetics of rapamycin: single-dose studies in the rabbit. Ther Drug Monit 14(6):475–478

    CAS  PubMed  Google Scholar 

  • Huang W, Zhu PJ, Zhang S, Zhou H, Stoica L, Galiano M, Krnjević K, Roman G, Costa-Mattioli M (2013) mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat Neurosci 16(4):441–448

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huynh TN, Santini E, Klann E (2014) Requirement of mammalian target of rapamycin complex 1 downstream effectors in cued fear memory reconsolidation and its persistence. J Neurosci 34(27):9034–9039

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huynh TN, Santini E, Mojica E, Fink AE, Hall BS, Fetcho RN, Grosenick L, Deisseroth K, LeDoux JE, Liston C, Klann E (2018) Activation of a novel p70 S6 kinase 1-dependent intracellular cascade in the basolateral nucleus of the amygdala is required for the acquisition of extinction memory. Mol Psychiatry 23(6):1394–1401

    CAS  PubMed  Google Scholar 

  • Izquierdo I, McGaugh JL (2000) Behavioural pharmacology and its contribution to the molecular basis of memory consolidation. Behav Pharmacol 11(7–8):517–534. https://doi.org/10.1097/00008877-200011000-00001

  • Izquierdo I, Bevilaqua LR, Rossato JI, Bonini JS, Medina JH, Cammarota M (2006) Different molecular cascades in different sites of the brain control memory consolidation. Trends Neurosci 29(9):496–505

    CAS  PubMed  Google Scholar 

  • James MH, Quinn RK, Ong LK, Levi EM, Smith DW, Dickson PW, Dayas CV (2016) Rapamycin reduces motivated responding for cocaine and alters GluA1 expression in the ventral but not dorsal striatum. Eur J Pharmacol 784:147–154

    CAS  PubMed  Google Scholar 

  • Jobim PF, Pedroso TR, Christoff RR, Werenicz A, Maurmann N, Reolon GK et al (2012a) Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory. Neurobiol Learn Mem 97(1):105–112

    CAS  PubMed  Google Scholar 

  • Jobim PF, Pedroso TR, Werenicz A, Christoff RR, Maurmann N, Reolon GK et al (2012b) Impairment of object recognition memory by rapamycin inhibition of mTOR in the amygdala or hippocampus around the time of learning or reactivation. Behav Brain Res 228(1):151–158

    CAS  PubMed  Google Scholar 

  • Jones AT, Yang J, Narov K, Henske EP, Sampson JR, Shen MH (2019) Allosteric and ATP-competitive inhibitors of mTOR effectively suppress tumor progression-associated epithelial-mesenchymal transition in the kidneys of Tsc2+/− mice. Neoplasia (New York, NY) 21(8):731–739

    CAS  Google Scholar 

  • Kahn J, Hayman TJ, Jamal M, Rath BH, Kramp T, Camphausen K, Tofilon PJ (2014) The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells. Neuro Oncol 16(1):29–37

    CAS  PubMed  Google Scholar 

  • Kelleher RJ 3rd, Govindarajan A, Jung HY, Kang H, Tonegawa S (2004) Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116(3):467–479

    CAS  PubMed  Google Scholar 

  • Lamming DW (2016) Inhibition of the mechanistic target of rapamycin (mTOR)-rapamycin and beyond. Cold Spring Harb Perspect Med 6(5):10.1101

    Google Scholar 

  • Lana D, Di Russo J, Mello T, Wenk GL, Giovannini MG (2017) Rapamycin inhibits mTOR/p70S6K activation in CA3 region of the hippocampus of the rat and impairs long term memory. Neurobiol Learn Mem 137:15–26

    CAS  PubMed  Google Scholar 

  • Lattal KM, Abel T (2004) Behavioral impairments caused by injections of the protein synthesis inhibitor anisomycin after contextual retrieval reverse with time. PNAS 101(13):4667–4672

    CAS  PubMed  Google Scholar 

  • Lay BPP, Westbrook RF, Glanzman DL, Holmes NM (2018) Commonalities and differences in the substrates underlying consolidation of first- and second-order conditioned fear. J Neurosci 38(8):1926–1941. https://doi.org/10.1523/JNEUROSCI.2966-17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacCallum PE, Hebert M, Adamec RE, Blundell J (2014) Systemic inhibition of mTOR kinase via rapamycin disrupts consolidation and reconsolidation of auditory fear memory. Neurobiol Learn Mem 112:176–185

    CAS  Google Scholar 

  • Martinez-Moreno A, Rodriguez-Duran LF, Escobar ML (2011) Late rrotein synthesis-dependent phases in CTA long-term Memory: BDNF Requirement. Front Behav Neurosci 5:61. https://doi.org/10.3389/fnbeh.2011.00061. eCollection 2011

  • McGaugh JL (2000) Memory--a century of consolidation. Science. 287(5451):248–251. https://doi.org/10.1126/science.287.5451.248

    Article  CAS  PubMed  Google Scholar 

  • Meiri N, Rosenblum K (1998) Lateral ventricle injection of the protein synthesis inhibitor Anisomycin impairs long-term memory in a spatial memory task. Brain Res 789(1):48–55. https://doi.org/10.1016/s0006-8993(97)01528-x

    Article  CAS  PubMed  Google Scholar 

  • Milekic MH, Pollonini G, Alberini CM (2007) Temporal requirement of C/EBPbeta in the amygdala following reactivation but not acquisition of inhibitory avoidance. Learn Mem 14(7):504–511. https://doi.org/10.1101/lm.598307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murray ER, Cameron AJM (2017) Towards specific inhibition of mTORC2. Aging 9(12):2461–2462

    PubMed  PubMed Central  Google Scholar 

  • Myskiw JC, Rossato JI, Bevilaqua LR, Medina JH, Izquierdo I, Cammarota M (2008) On the participation of mTOR in recognition memory. Neurobiol Learn Mem 89(3):338–351

    CAS  PubMed  Google Scholar 

  • Neasta J, Barak S, Hamida SB, Ron D (2014) mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse. J Neurochem 130(2):172–184

    CAS  PubMed  PubMed Central  Google Scholar 

  • Parsons RG, Gafford GM, Helmstetter FJ (2006) Translational control via the mammalian target of rapamycin pathway is critical for the formation and stability of long-term fear memory in amygdala neurons. J Neurosci 26(50):12977–12983

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pearce LR, Alton GR, Richter DT, Kath JC, Lingardo L, Chapman J, Hwang C, Alessi DR (2010) Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem J 431(2):245–255

    CAS  PubMed  Google Scholar 

  • Pena RR, Pereira-Caixeta AR, Moraes MF, Pereira GS (2014) Anisomycin administered in the olfactory bulb and dorsal hippocampus impaired social recognition memory consolidation in different time-points. Brain Res Bull 109:151–157

    CAS  PubMed  Google Scholar 

  • Powles T, Wheater M, Din O, Geldart T, Boleti E, Stockdale A, Sundar S, Robinson A, Ahmed I, Wimalasingham A, Burke W, Sarker SJ, Hussain S, Ralph C (2016) A randomised phase 2 study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer. Eur Urol 69(3):450–456

    CAS  PubMed  Google Scholar 

  • Quevedo J, Vianna MR, Roesler R, de Paris F, Izquierdo I, Rose SP (1999) Two time windows of anisomycin-induced amnesia for inhibitory avoidance training in rats: protection from amnesia by pretraining but not pre-exposure to the task apparatus. Learn Mem 6(6):600–607

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rodriguez-Ortiz CJ, Bermudez-Rattoni F (2007) Memory reconsolidation or updating consolidation? In: Bermudez-Rattoni F (ed) Neural plasticity and memory: from genes to brain imaging. Boca Raton, Taylor & Francis Group

    Google Scholar 

  • Rossato JI, Bevilaqua LR, Myskiw JC, Medina JH, Izquierdo I, Cammarota M (2007) On the role of hippocampal protein synthesis in the consolidation and reconsolidation of object recognition memory. Learn Mem 14(1):36–46

    PubMed  PubMed Central  Google Scholar 

  • Ryan TJ, Roy DS, Pignatelli M, Arons A, Tonegawa S (2015) Memory. Engram cells retain memory under retrograde amnesia. Science 348(6238):1007–1013. https://doi.org/10.1126/science.aaa5542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sabatini DM (2017) Twenty-five years of mTOR: uncovering the link from nutrients to growth. PNAS 114(45):11818–11825

    CAS  PubMed  Google Scholar 

  • Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22(2):159–168

    CAS  PubMed  Google Scholar 

  • Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 169(2):361–371

    CAS  PubMed  Google Scholar 

  • Sengupta S, Peterson TR, Sabatini DM (2010) Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 40(2):310–322

    CAS  PubMed  PubMed Central  Google Scholar 

  • Slipczuk L, Bekinschtein P, Katche C, Cammarota M, Izquierdo I, Medina JH (2009) BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS One 4(6):e6007

    PubMed  PubMed Central  Google Scholar 

  • Sossin WS (2008) Molecular memory traces. Prog Brain Res 169:3–25

    CAS  PubMed  Google Scholar 

  • 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. PNAS 108(9):3791–3796

    CAS  PubMed  Google Scholar 

  • Sui L, Wang J, Li BM (2008) Role of the phosphoinositide 3-kinase-akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex. Learn Mem 15(10):762–776

    CAS  PubMed  Google Scholar 

  • Sun T, Liu Z, Liu M, Guo Y, Sun H, Zhao J, Lan Z, Lian B, Zhang J (2019) Hippocampus-specific rictor knockdown inhibited 17beta-estradiol induced neuronal plasticity and spatial memory improvement in ovariectomized mice. Behav Brain Res 364:50–61

    CAS  PubMed  Google Scholar 

  • Supko JG, Malspeis L (1994) Dose-dependent pharmacokinetics of rapamycin-28-N,N-dimethylglycinate in the mouse. Cancer Chemother Pharmacol 33(4):325–330

    CAS  PubMed  Google Scholar 

  • Teh JLF, Cheng PF, Purwin TJ, Nikbakht N, Patel P, Chervoneva I, Ertel A, Fortina PM, Kleiber I, HooKim K, Davies MA, Kwong LN, Levesque MP, Dummer R, Aplin AE (2018) In vivo E2F reporting reveals efficacious schedules of MEK1/2-CDK4/6 targeting and mTOR-S6 resistance mechanisms. Cancer Discov 8(5):568–581

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284(12):8023–8032

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wanisch K, Wotjak CT, Engelmann M (2008) Long-lasting second stage of recognition memory consolidation in mice. Behav Brain Res 186(2):191–196. https://doi.org/10.1016/j.bbr.2007.08.008

  • Werfel TA, Wang S, Jackson MA, Kavanaugh TE, Joly MM, Lee LH, Hicks DJ, Sanchez V, Ericsson PG, Kilchrist KV, Dimobi SC, Sarett SM, Brantley-Sieders DM, Cook RS, Duvall CL (2018) Selective mTORC2 inhibitor therapeutically blocks breast cancer cell growth and survival. Cancer Res 78(7):1845–1858

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yu K, Toral-Barza L, Shi C, Zhang WG, Lucas J, Shor B, Kim J, Verheijen J, Curran K, Malwitz DJ, Cole DC, Ellingboe J, Ayral-Kaloustian S, Mansour TS, Gibbons JJ, Abraham RT, Nowak P, Zask A (2009) Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 69(15):6232–6240

    CAS  PubMed  Google Scholar 

  • Zhao B, Sun J, Zhang X, Mo H, Niu Y, Li Q, Wang L, Zhong Y (2019) Long-term memory is formed immediately without the need for protein synthesis-dependent consolidation in drosophila. Nat Commun 10(1):4550

    PubMed  PubMed Central  Google Scholar 

  • Zhong H, Fazenbaker C, Breen S, Chen C, Huang J, Morehouse C, Yao Y, Hollingsworth RE (2014) MEDI-573, alone or in combination with mammalian target of rapamycin inhibitors, targets the insulin-like growth factor pathway in sarcomas. Mol Cancer Ther 13(11):2662–2673

    CAS  PubMed  Google Scholar 

  • Zhu PJ, Chen CJ, Mays J, Stoica L, Costa-Mattioli M (2018) mTORC2, but not mTORC1, is required for hippocampal mGluR-LTD and associated behaviors. Nat Neurosci 21(6):799–802

    CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Psychology, Memorial University of Newfoundland, St. John’s, NL, Canada

    Phillip E. MacCallum & Jacqueline Blundell

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MacCallum, P.E., Blundell, J. The mTORC1 inhibitor rapamycin and the mTORC1/2 inhibitor AZD2014 impair the consolidation and persistence of contextual fear memory. Psychopharmacology 237, 2795–2808 (2020). https://doi.org/10.1007/s00213-020-05573-1

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