Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Reviews in the Neurosciences

Editor-in-Chief: Huston, Joseph P.

Editorial Board: Topic, Bianca / Adeli, Hojjat / Buzsaki, Gyorgy / Crawley, Jacqueline / Crow, Tim / Gold, Paul / Holsboer, Florian / Korth, Carsten / Li, Jay-Shake / Lubec, Gert / McEwen, Bruce / Pan, Weihong / Pletnikov, Mikhail / Robbins, Trevor / Schnitzler, Alfons / Stevens, Charles / Steward, Oswald / Trojanowski, John

IMPACT FACTOR 2017: 2.590
5-year IMPACT FACTOR: 3.078

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 0.980
Source Normalized Impact per Paper (SNIP) 2017: 0.804

See all formats and pricing
More options …
Volume 25, Issue 4


Does autophagy work in synaptic plasticity and memory?

Mohammad Shehata
  • Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
  • Japan Science and Technology Agency (JST), CREST, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
  • Faculty of Pharmacy, Department of Biochemistry, Cairo University, Kasr El-Aini, Cairo 11562, Egypt
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Kaoru Inokuchi
  • Corresponding author
  • Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
  • Japan Science and Technology Agency (JST), CREST, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2014-03-21 | DOI: https://doi.org/10.1515/revneuro-2014-0002


Many studies have reported the roles played by regulated proteolysis in neural plasticity and memory. Within this context, most of the research focused on the ubiquitin-proteasome system and the endosome-lysosome system while giving lesser consideration to another major protein degradation system, namely, autophagy. Although autophagy intersects with many of the pathways known to underlie synaptic plasticity and memory, only few reports related autophagy to synaptic remodeling. These pathways include PI3K-mTOR pathway and endosome-dependent proteolysis. In this review, we will discuss several lines of evidence supporting a physiological role of autophagy in memory processes, and the possible mechanistic scenarios for how autophagy could fulfill this function.

Keywords: AMPA receptors; autophagy; memory; NMDA receptors; synaptic plasticity


  • Abel, T., Martin, K.C., Bartsch, D., and Kandel, E.R. (1998). Memory suppressor genes: inhibitory constraints on the storage of long-term memory. Science 279, 338–341.Google Scholar

  • Alirezaei, M., Kemball, C.C., Flynn, C.T., Wood, M.R., Whitton, J.L., and Kiosses, W.B. (2010). Short-term fasting induces profound neuronal autophagy. Autophagy 6, 702–710.PubMedCrossrefGoogle Scholar

  • Antion, M.D., Hou, L., Wong, H., Hoeffer, C.A., and 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.CrossrefGoogle Scholar

  • Barros, D.M., Mello e Souza, T., de Souza, M.M., Choi, H., DeDavid e Silva, T., Lenz, G., Medina, J.H., and Izquierdo, I. (2001). LY294002, an inhibitor of phosphoinositide 3-kinase given into rat hippocampus impairs acquisition, consolidation and retrieval of memory for one-trial step-down inhibitory avoidance. Behav. Pharmacol. 12, 629–634.CrossrefGoogle Scholar

  • Bekinschtein, P., Katche, C., Slipczuk, L.N., Igaz, L.M., Cammarota, M., Izquierdo, I., and Medina, J.H. (2007). mTOR signaling in the hippocampus is necessary for memory formation. Neurobiol. Learn Mem. 87, 303–307.PubMedCrossrefGoogle Scholar

  • Bingol, B. and Sheng, M. (2011). Deconstruction for reconstruction: the role of proteolysis in neural plasticity and disease. Neuron 69, 22–32.CrossrefPubMedGoogle Scholar

  • Bliss, T.V. and Collingridge, G.L. (2013). Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide. Mol. Brain 6, 5.PubMedCrossrefGoogle Scholar

  • Bliss, T.V., Collingridge, G.L., and Morris, R.G. (2003). Introduction. Long-term potentiation and structure of the issue. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 358, 607–611.Google Scholar

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

  • Boland, B., Kumar, A., Lee, S., Platt, F.M., Wegiel, J., Yu, W.H., and Nixon, R.A. (2008). Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J. Neurosci. 28, 6926–6937.CrossrefGoogle Scholar

  • Cammalleri, M., Lutjens, R., Berton, F., King, A.R., Simpson, C., Francesconi, W., and Sanna, P.P. (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, 14368–14373.CrossrefGoogle Scholar

  • Cantley, L.C. (2002). The phosphoinositide 3-kinase pathway. Science 296, 1655–1657.Google Scholar

  • Carloni, S., Buonocore, G., and Balduini, W. (2008). Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol. Dis. 32, 329–339.PubMedCrossrefGoogle Scholar

  • Carloni, S., Girelli, S., Scopa, C., Buonocore, G., Longini, M., and Balduini, W. (2010). Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia. Autophagy 6, 366–377.PubMedCrossrefGoogle Scholar

  • Casadio, A., Martin, K.C., Giustetto, M., Zhu, H., Chen, M., Bartsch, D., Bailey, C.H., and Kandel, E.R. (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.CrossrefPubMedGoogle Scholar

  • Chan, E.Y. (2009). mTORC1 phosphorylates the ULK1-mAtg13-FIP200 autophagy regulatory complex. Sci. Signal 18; 2(84) pe51.Google Scholar

  • Chen, Y. and Klionsky, D.J. (2011). The regulation of autophagy – unanswered questions. J. Cell Sci. 124, 161–170.CrossrefGoogle Scholar

  • Chen, X., Garelick, M.G., Wang, H., Lil, V., Athos, J., and Storm, D.R. (2005). PI3 kinase signaling is required for retrieval and extinction of contextual memory. Nat. Neurosci. 8, 925–931.CrossrefGoogle Scholar

  • Cheung, Z.H. and Ip, N.Y. (2009). The emerging role of autophagy in Parkinson’s disease. Mol. Brain 2, 29.CrossrefPubMedGoogle Scholar

  • Ciechanover, A. (2005). Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat. Rev. Mol. Cell Biol. 6, 79–87.CrossrefPubMedGoogle Scholar

  • Collingridge, G.L. and Bliss, T.V. (1995). Memories of NMDA receptors and LTP. Trends Neurosci. 18, 54–56.CrossrefPubMedGoogle Scholar

  • Collingridge, G.L., Isaac, J.T., and Wang, Y.T. (2004). Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5, 952–962.PubMedCrossrefGoogle Scholar

  • Collingridge, G.L., Peineau, S., Howland, J.G., and Wang, Y.T. (2010). Long-term depression in the CNS. Nat. Rev. Neurosci. 11, 459–473.PubMedCrossrefGoogle Scholar

  • Dash, P.K., Mach, S.A., Blum, S., and Moore, A.N. (2002). Intrahippocampal wortmannin infusion enhances long-term spatial and contextual memories. Learn Mem. 9, 167–177.PubMedGoogle Scholar

  • Davis, H.P. and Squire, L.R. (1984). Protein synthesis and memory: a review. Psychol. Bull 96, 518–559.CrossrefPubMedGoogle Scholar

  • Dikic, I., Johansen, T., and Kirkin, V. (2010). Selective autophagy in cancer development and therapy. Cancer Res. 70, 3431–3434.CrossrefPubMedGoogle Scholar

  • Ehlers, M.D. (2000). Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28, 511–525.CrossrefPubMedGoogle Scholar

  • Fader, C.M. and Colombo, M.I. (2009). Autophagy and multivesicular bodies: two closely related partners. Cell Death Differ. 16, 70–78.CrossrefGoogle Scholar

  • Fass, E., Shvets, E., Degani, I., Hirschberg, K., and Elazar, Z. (2006). Microtubules support production of starvation-induced autophagosomes but not their targeting and fusion with lysosomes. J. Biol. Chem. 281, 36303–36316.Google Scholar

  • Fleming, A., Noda, T., Yoshimori, T., and Rubinsztein, D.C. (2010). Chemical modulators of autophagy as biological probes and potential therapeutics. Nat. Chem. Biol. 7, 9–17.Google Scholar

  • Franke, T.F. and Cantley, L.C. (1997). Apoptosis. A Bad kinase makes good. Nature 390, 116–117.Google Scholar

  • Gafford, G.M., Parsons, R.G., and Helmstetter, F.J. (2011). Consolidation and reconsolidation of contextual fear memory requires mammalian target of rapamycin-dependent translation in the dorsal hippocampus. Neuroscience 182, 98–104.PubMedCrossrefGoogle Scholar

  • Gingras, A.C., Kennedy, S.G., O’Leary, M.A., Sonenberg, N., and Hay, N. (1998). 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt (PKB) signaling pathway. Genes Dev. 12, 502–513.CrossrefGoogle Scholar

  • Glover, E.M., Ressler, K.J., and Davis, M. (2010). Differing effects of systemically administered rapamycin on consolidation and reconsolidation of context vs. cued fear memories. Learn Mem. 17, 577–581.PubMedGoogle Scholar

  • Goldberg, A.L. and St John, A.C. (1976). Intracellular protein degradation in mammalian and bacterial cells: Part 2. Annu. Rev. Biochem. 45, 747–803.CrossrefGoogle Scholar

  • Hailey, D.W., Rambold, A.S., Satpute-Krishnan, P., Mitra, K., Sougrat, R., Kim, P.K., and Lippincott-Schwartz, J. (2010). Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141, 656–667.Google Scholar

  • Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889.Google Scholar

  • Hay, N. and Sonenberg, N. (2004). Upstream and downstream of mTOR. Genes Dev. 18, 1926–1945.CrossrefPubMedGoogle Scholar

  • Hegde, A.N., Goldberg, A.L., and Schwartz, J.H. (1993). Regulatory subunits of cAMP-dependent protein kinases are degraded after conjugation to ubiquitin: a molecular mechanism underlying long-term synaptic plasticity. Proc. Natl. Acad. Sci. USA 90, 7436–7440.CrossrefGoogle Scholar

  • Hegde, A.N., Inokuchi, K., Pei, W., Casadio, A., Ghirardi, M., Chain, D.G., Martin, K.C., Kandel, E.R., and Schwartz, J.H. (1997). Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. Cell 89, 115–126.Google Scholar

  • Hirling, H. (2009). Endosomal trafficking of AMPA-type glutamate receptors. Neuroscience 158, 36–44.Google Scholar

  • Hoeffer, C.A. and Klann, E. (2009). mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33, 67–75.PubMedGoogle Scholar

  • Hollenbeck, P.J. (1993). Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. J. Cell Biol. 121, 305–315.CrossrefPubMedGoogle Scholar

  • Honore, T., Lauridsen, J., and Krogsgaard-Larsen, P. (1982). The binding of [3H]AMPA, a structural analogue of glutamic acid, to rat brain membranes. J. Neurochem. 38, 173–178.CrossrefGoogle Scholar

  • Horwood, J.M., Dufour, F., Laroche, S., and Davis, S. (2006). Signalling mechanisms mediated by the phosphoinositide 3-kinase/Akt cascade in synaptic plasticity and memory in the rat. Eur. J. Neurosci. 23, 3375–3384.PubMedCrossrefGoogle Scholar

  • Hosokawa, N., Hara, T., Kaizuka, T., Kishi, C., Takamura, A., Miura, Y., Iemura, S., Natsume, T., Takehana, K., Yamada, N., et al. (2009). Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991.Google Scholar

  • 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.CrossrefGoogle Scholar

  • Itakura, E. and Mizushima, N. (2010). Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 6, 764–776.CrossrefPubMedGoogle Scholar

  • Jaeger, P.A. and Wyss-Coray, T. (2009). All-you-can-eat: autophagy in neurodegeneration and neuroprotection. Mol. Neurodegener. 4, 16.PubMedCrossrefGoogle Scholar

  • Jiang, J., Parameshwaran, K., Seibenhener, M.L., Kang, M.G., Suppiramaniam, V., Huganir, R.L., Diaz-Meco, M.T., and Wooten, M.W. (2009). AMPA receptor trafficking and synaptic plasticity require SQSTM1/p62. Hippocampus 19, 392–406.CrossrefGoogle Scholar

  • Jobim, P.F., Pedroso, T.R., Christoff, R.R., Werenicz, A., Maurmann, N., Reolon, G.K., and Roesler, R. (2011). Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory. Neurobiol. Learn Mem. 97, 105–112.PubMedGoogle Scholar

  • Johansen, J.P., Cain, C.K., Ostroff, L.E., and LeDoux, J.E. (2011). Molecular mechanisms of fear learning and memory. Cell 147, 509–524.Google Scholar

  • Jung, C.H., Jun, C.B., Ro, S.H., Kim, Y.M., Otto, N.M., Cao, J., Kundu, M., and Kim, D.H. (2009). ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992–2003.CrossrefGoogle Scholar

  • Jurado, S., Benoist, M., Lario, A., Knafo, S., Petrok, C.N., and Esteban, J.A. (2010). PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression. EMBO J. 29, 2827–2840.PubMedCrossrefGoogle Scholar

  • Kandel, E.R. (2001). The molecular biology of memory storage: a dialog between genes and synapses. Biosci. Rep. 21, 565–611.PubMedCrossrefGoogle Scholar

  • Kandel, E.R. (2012). The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol. Brain 5, 14.CrossrefGoogle Scholar

  • Katso, R., Okkenhaug, K., Ahmadi, K., White, S., Timms, J., and Waterfield, M.D. (2001). Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 17, 615–675.CrossrefPubMedGoogle Scholar

  • Kaushik, S., Rodriguez-Navarro, J.A., Arias, E., Kiffin, R., Sahu, S., Schwartz, G.J., Cuervo, A.M., and Singh, R. (2011). Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab. 14, 173–183.CrossrefPubMedGoogle Scholar

  • Kelleher, R.J., 3rd, Govindarajan, A., and Tonegawa, S. (2004a). Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44, 59–73.CrossrefGoogle Scholar

  • Kelleher, R.J., 3rd, Govindarajan, A., Jung, H.Y., Kang, H., and Tonegawa, S. (2004b). Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467–479.CrossrefGoogle Scholar

  • Kelly, A. and Lynch, M.A. (2000). Long-term potentiation in dentate gyrus of the rat is inhibited by the phosphoinositide 3-kinase inhibitor, wortmannin. Neuropharmacology 39, 643–651.CrossrefGoogle Scholar

  • Kirkin, V. and Dikic, I. (2010). Ubiquitin networks in cancer. Curr. Opin. Genet. Dev. 21, 21–28.PubMedGoogle Scholar

  • Klann, E. and Dever, T.E. (2004). Biochemical mechanisms for translational regulation in synaptic plasticity. Nat. Rev. Neurosci. 5, 931–942.CrossrefPubMedGoogle Scholar

  • Klionsky, D.J., Cregg, J.M., Dunn, W.A., Jr., Emr, S.D., Sakai, Y., Sandoval, I.V., Sibirny, A., Subramani, S., Thumm, M., Veenhuis, M., et al. (2003). A unified nomenclature for yeast autophagy-related genes. Dev. Cell 5, 539–545.CrossrefPubMedGoogle Scholar

  • Klionsky, D.J., Abdalla, F.C., Abeliovich, H., Abraham, R.T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J.A. et al. (2012). Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445–544.PubMedCrossrefGoogle Scholar

  • Kochl, R., Hu, X.W., Chan, E.Y., and Tooze, S.A. (2006). Microtubules facilitate autophagosome formation and fusion of autophagosomes with endosomes. Traffic 7, 129–145.PubMedCrossrefGoogle Scholar

  • Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., et al. (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884.Google Scholar

  • Komatsu, M., Wang, Q.J., Holstein, G.R., Friedrich, V.L., Jr., Iwata, J., Kominami, E., Chait, B.T., Tanaka, K., and Yue, Z. (2007a). Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Natl. Acad. Sci. USA 104, 14489–14494.CrossrefGoogle Scholar

  • Komatsu, M., Wang, Q.J., Holstein, G.R., Friedrich, V.L., Jr., Iwata, J., Kominami, E., Chait, B.T., Tanaka, K., and Yue, Z. (2007b). Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163.Google Scholar

  • Kraft, C., Peter, M., and Hofmann, K. (2010). Selective autophagy: ubiquitin-mediated recognition and beyond. Nat. Cell Biol. 12, 83–841.Google Scholar

  • Lawrence, J.C., Lin, T.A., McMahon, L.P., and Choi, K.M. (2004). Modulation of the protein kinase activity of mTOR. Curr. Top. Microbiol. Immunol. 279, 199–213.Google Scholar

  • Lee, Y.S. and Silva, A.J. (2009). The molecular and cellular biology of enhanced cognition. Nat. Rev. Neurosci. 10, 126–140.CrossrefPubMedGoogle Scholar

  • Lee, S.H., Simonetta, A., and Sheng, M. (2004). Subunit rules governing the sorting of internalized AMPA receptors in hippocampal neurons. Neuron 43, 221–236.PubMedCrossrefGoogle Scholar

  • Lee, J.H., Yu, W.H., Kumar, A., Lee, S., Mohan, P.S., Peterhoff, C.M., Wolfe, D.M., Martinez-Vicente, M., Massey, A.C., Sovak, G., et al. (2010). Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158.Google Scholar

  • Li, Y., Meloni, E.G., Carlezon, W.A., Jr., Milad, M.R., Pitman, R.K., Nader, K., and Bolshakov, V.Y. (2013). Learning and reconsolidation implicate different synaptic mechanisms. Proc. Natl. Acad. Sci. USA 110, 4798–4803.CrossrefGoogle Scholar

  • Lin, C.H., Yeh, S.H., Lu, K.T., Leu, T.H., Chang, W.C., and Gean, P.W. (2001). A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron 31, 841–851.PubMedCrossrefGoogle Scholar

  • Majumder, S., Richardson, A., Strong, R., and Oddo, S. (2011). Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One 6(9), e25416.Google Scholar

  • Malenka, R.C. and Bear, M.F. (2004). LTP and LTD: an embarrassment of riches. Neuron 44, 5–21.CrossrefPubMedGoogle Scholar

  • Mayford, M., Siegelbaum, S.A., and Kandel, E.R. (2012). Synapses and memory storage. Cold Spring Harb. Perspect. Biol. 4:a005751.Google Scholar

  • Mizuno, M., Yamada, K., Takei, N., Tran, M.H., He, J., Nakajima, A., Nawa, H., and Nabeshima, T. (2003). Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation. Mol. Psychiatry 8, 217–224.PubMedGoogle Scholar

  • Mizushima, N. (2007). Autophagy: process and function. Genes Dev. 21, 2861–2873.CrossrefPubMedGoogle Scholar

  • Mizushima, N. and Yoshimori, T. (2007). How to interpret LC3 immunoblotting? Autophagy 3, 542–545.Google Scholar

  • Mizushima, N. and Komatsu, M. (2011). Autophagy: renovation of cells and tissues. Cell 147, 728–741.Google Scholar

  • Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T., and Ohsumi, Y. (2004). In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101–1111.PubMedGoogle Scholar

  • Mizushima, N., Yoshimori, T., and Levine, B. (2010). Methods in mammalian autophagy research. Cell 140, 313–326.Google Scholar

  • Mizushima, N., Yoshimori, T., and Ohsumi, Y. (2011). The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132.PubMedCrossrefGoogle Scholar

  • Mulkey, R.M., Herron, C.E., and Malenka, R.C. (1993). An essential role for protein phosphatases in hippocampal long-term depression. Science 261, 1051–1055.Google Scholar

  • Myskiw, J.C., Rossato, J.I., Bevilaqua, L.R., Medina, J.H., Izquierdo, I., and Cammarota, M. (2008). On the participation of mTOR in recognition memory. Neurobiol. Learn Mem. 89, 338–351.PubMedCrossrefGoogle Scholar

  • Nader, K., Schafe, G.E., and Le Doux, J.E. (2000). Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726.Google Scholar

  • Nakatogawa, H., Suzuki, K., Kamada, Y., and Ohsumi, Y. (2009). Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat. Rev. Mol. Cell Biol. 10, 458–467.CrossrefPubMedGoogle Scholar

  • Nishiyama, J., Miura, E., Mizushima, N., Watanabe, M., and Yuzaki, M. (2007). Aberrant membranes and double-membrane structures accumulate in the axons of Atg5-null Purkinje cells before neuronal death. Autophagy 3, 591–596.PubMedCrossrefGoogle Scholar

  • Nixon, R.A., Yang, D.S., and Lee, J.H. (2008). Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 4, 590–599.CrossrefPubMedGoogle Scholar

  • Opazo, P., Watabe, A.M., Grant, S.G., and O′Dell, T.J. (2003). Phosphatidylinositol 3-kinase regulates the induction of long-term potentiation through extracellular signal-related kinase-independent mechanisms. J. Neurosci. 23, 3679–3688.Google Scholar

  • Palmer, M.J., Irving, A.J., Seabrook, G.R., Jane, D.E., and Collingridge, G.L. (1997). The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus. Neuropharmacology 36, 1517–1532.CrossrefGoogle Scholar

  • Parsons, R.G., Gafford, G.M., and Helmstetter, F.J. (2006). Translational control via the mammalian target of rapamycin pathway is critical for the formation and stability of long-term fear memory in amygdala neurons. J. Neurosci. 26, 12977–12983.CrossrefGoogle Scholar

  • Pittenger, C. and Kandel, E.R. (2003). In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 358, 757–763.CrossrefGoogle Scholar

  • Pullen, N. and Thomas, G. (1997). The modular phosphorylation and activation of p70s6k. FEBS Lett. 410, 78–82.Google Scholar

  • Quirk, G.J. and Mueller, D. (2008). Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33, 56–72.PubMedCrossrefGoogle Scholar

  • Ramesh Babu, J., Lamar Seibenhener, M., Peng, J., Strom, A.L., Kemppainen, R., Cox, N., Zhu, H., Wooten, M.C., Diaz-Meco, M.T., Moscat, J., et al. (2008). Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. J. Neurochem. 106, 107–120.CrossrefGoogle Scholar

  • Ravikumar, B., Futter, M., Jahreiss, L., Korolchuk, V.I., Lichtenberg, M., Luo, S., Massey, D.C., Menzies, F.M., Narayanan, U., Renna, M., et al. (2009). Mammalian macroautophagy at a glance. J. Cell Sci. 122, 1707–1711.CrossrefGoogle Scholar

  • Ravikumar, B., Moreau, K., Jahreiss, L., Puri, C., and Rubinsztein, D.C. (2010). Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat. Cell Biol. 12, 747–757.CrossrefPubMedGoogle Scholar

  • Rowland, A.M., Richmond, J.E., Olsen, J.G., Hall, D.H., and Bamber, B.A. (2006). Presynaptic terminals independently regulate synaptic clustering and autophagy of GABAA receptors in Caenorhabditis elegans. J. Neurosci. 26, 1711–1720.CrossrefGoogle Scholar

  • Rubinsztein, D.C. (2006). The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780–786.Google Scholar

  • Rubinsztein, D.C., Gestwicki, J.E., Murphy, L.O., and Klionsky, D.J. (2007). Potential therapeutic applications of autophagy. Nat. Rev. Drug Discov. 6, 304–312.CrossrefPubMedGoogle Scholar

  • Sanna, P.P., Cammalleri, M., Berton, F., Simpson, C., Lutjens, R., Bloom, F.E., and Francesconi, W. (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.Google Scholar

  • Sarbassov, D.D., Guertin, D.A., Ali, S.M., and Sabatini, D.M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101.Google Scholar

  • Shehata, M., Matsumura, H., Okubo-Suzuki, R., Ohkawa, N., and Inokuchi, K. (2012) Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. J. Neurosci. 32, 10413–10422.CrossrefGoogle Scholar

  • Shen, W. and Ganetzky, B. (2009). Autophagy promotes synapse development in Drosophila. J. Cell Biol. 187, 71–79.Google Scholar

  • Shepherd, J.D. and Huganir, R.L. (2007). The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu. Rev. Cell Dev. Biol. 23, 613–643.PubMedCrossrefGoogle Scholar

  • Shi, S., Hayashi, Y., Esteban, J.A., and Malinow, R. (2001). Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105, 331–343.PubMedCrossrefGoogle Scholar

  • Stoica, L., Zhu, P.J., Huang, W., Zhou, H., Kozma, S.C., and 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, 3791–3796.CrossrefGoogle Scholar

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

  • Suzuki, K. and Ohsumi, Y. (2007). Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. FEBS Lett. 581, 2156–2161.Google Scholar

  • Tada, T. and Sheng, M. (2006). Molecular mechanisms of dendritic spine morphogenesis. Curr. Opin. Neurobiol. 16, 95–101.PubMedCrossrefGoogle Scholar

  • Takei, N., Inamura, N., Kawamura, M., Namba, H., Hara, K., Yonezawa, K., and Nawa, H. (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.CrossrefGoogle Scholar

  • 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.CrossrefGoogle Scholar

  • Tooze, S.A. and Yoshimori, T. (2010). The origin of the autophagosomal membrane. Nat. Cell Biol. 12, 831–835.CrossrefPubMedGoogle Scholar

  • Tronson, N.C. and Taylor, J.R. (2007). Molecular mechanisms of memory reconsolidation. Nat. Rev. Neurosci. 8, 262–275.PubMedCrossrefGoogle Scholar

  • Wenthold, R.J., Petralia, R.S., Blahos, J., II, and Niedzielski, A.S. (1996). Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons. J. Neurosci. 16, 1982–1989.Google Scholar

  • Xie, Z. and Klionsky, D.J. (2007). Autophagosome formation: core machinery and adaptations. Nat. Cell Biol. 9, 1102–1109.PubMedCrossrefGoogle Scholar

About the article

Mohammad Shehata

Mohammad Shehata graduated with a Bachelor’s degree in Pharmaceutical Sciences from the Faculty of Pharmacy, Cairo University, Egypt in 2001 and then affiliated to work as staff member in the Department of Biochemistry. He earned his PhD from the Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan in 2011. He continued his postdoctoral studies working as an Assistant Professor in the Biochemistry Department, Faculty of Medicine, University of Toyama. His research is focusing the role of protein degradation mechanisms, specifically autophagy, in synaptic plasticity and memory. His works aims to understand how memories are weakened or completely forgotten which might be useful to find remedies for diseases such as post-traumatic stress disorder (PTSD).

Kaoru Inokuchi

Kaoru Inokuchi earned his PhD from Nagoya University, Japan in 1985. After a postdoc training in the laboratory of Eric Kandel at Columbia University, NY, he became a group director at MITILS in 1993. He is a Professor in the Department of Biochemistry, Faculty of Medicine, University of Toyama, Japan. His work aims to understand the molecular, cellular, and circuit mechanisms underlying memory storage in the brain.

Corresponding author: Kaoru Inokuchi, Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan; and Japan Science and Technology Agency (JST), CREST, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan, e-mail:

Received: 2014-01-07

Accepted: 2014-02-17

Published Online: 2014-03-21

Published in Print: 2014-08-01

Citation Information: Reviews in the Neurosciences, Volume 25, Issue 4, Pages 543–557, ISSN (Online) 2191-0200, ISSN (Print) 0334-1763, DOI: https://doi.org/10.1515/revneuro-2014-0002.

Export Citation

© 2014 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Kareem Abdou, Mohammad Shehata, Kiriko Choko, Hirofumi Nishizono, Mina Matsuo, Shin-ichi Muramatsu, and Kaoru Inokuchi
Science, 2018, Volume 360, Number 6394, Page 1227
Jorge Montesinos, María Pascual, David Millán-Esteban, and Consuelo Guerri
Neuroscience Letters, 2018
N. V. Gulyaeva
Biochemistry (Moscow), 2017, Volume 82, Number 3, Page 237
Jameson Patak, Jonathan L. Hess, Yanli Zhang-James, Stephen J. Glatt, and Stephen V. Faraone
Autism Research, 2017, Volume 10, Number 3, Page 414
Andrea K.H. Stavoe, Sarah E. Hill, David H. Hall, and Daniel A. Colón-Ramos
Developmental Cell, 2016, Volume 38, Number 2, Page 171
Reiko Okubo-Suzuki, Yoshito Saitoh, Mohammad Shehata, Qi Zhao, Hiroshi Enomoto, and Kaoru Inokuchi
Molecular Brain, 2016, Volume 9, Number 1
Y Xi, J S Dhaliwal, M Ceizar, M Vaculik, K L Kumar, and D C Lagace
Cell Death and Disease, 2016, Volume 7, Number 3, Page e2127
Alireza Sarkaki, Yaghoob Farbood, Mohammad Badavi, Leila Khalaj, Fariba Khodagholi, and Ghorbangol Ashabi
Metabolic Brain Disease, 2015, Volume 30, Number 5, Page 1139
Dale D.O. Martin, Safia Ladha, Dagmar E. Ehrnhoefer, and Michael R. Hayden
Trends in Neurosciences, 2015, Volume 38, Number 1, Page 26

Comments (0)

Please log in or register to comment.
Log in