Українська English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2021; 67(6): 74-83


A.O. Nastenko, N.S. Veselovsky

    Bogomoletz Institute of Physiology NAS of Ukraine, Kyiv, Ukraine


Long-term potentiation is involved in the mechanisms of synaptic plasticity, provides such processes as memory and learning, and allows the nervous system of a living organism to adapt to changing environmental conditions. It is an increase in the efficiency of glutamatergic synapses, which lasts much longer than other types of potentiation in the nervous system. Despite the fact that long-term potentiation has been studied in detail, the physiological mechanisms of its formation, which lead to an increase of synaptic weight, remain incompletely understood. Well known that long-term potentiation is closely dependent on the processes of rapid axonal transport. However, how axonal transport is related to the mechanisms of long-term potentiation induction and expression, what substances are transported through axons, and how they affect the synaptic activity of postsynaptic neurons is currently unknown. We review here the main physiological mechanisms that occur in the neurons of the hippocampus and contribute to the formation of long-term potentiation. The works of recent years devoted to the study of the participation of synaptic tagging, retrograde signaling, morphological modifications and axonal transport in formation of the long-term potentiation are analyzed.

Keywords: long-term potentiation; synaptic tagging; retro- grade signaling; morphological modifications; axonal tran- sport.


  1. Lomo T. Frequency potentiation of excitatory synaptic activity in the dentate area of the hippocampal formation. Acta Physiol Scand. 1966;68(277):128.
  2. Cooke SF, Bliss TV. Plasticity in the human central nervous system. Brain. 2006 Jul;129(7):1659-73. CrossRef PubMed
  3. Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron. 2004 Sep;44(1):5-21. CrossRef PubMed
  4. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993 Jan;361(6407):31-9. CrossRef PubMed
  5. Lynch MA. Long-term potentiation and memory. Physiol Rev. 2004 Jan;84(1):87-136. CrossRef PubMed
  6. Abraham WC. How long will long-term potentia- tion last? Philos Trans R Soc Lond B Biol Sci. 2003 Apr;358(1432):735-44. CrossRef PubMed PubMedCentral
  7. Molnár E. Long-term potentiation in cultured hippocampal neurons. Semin Cell Dev Biol. 2011 Jul;22(5):506-13. CrossRef PubMed
  8. Sweatt JD. Toward a molecular explanation for long-term potentiation. Learn Mem. 1999 Sep-Oct;6(5):399-416. CrossRef PubMed
  9. Collingridge GL, Kehl SJ, McLennan H. Excitatory amino acids in synaptic transmission in the Schaffer collateral- commissural pathway of the rat hippocampus. J Physiol. 1983 Jan;334:33-46. CrossRef PubMed PubMedCentral
  10. Kovács KA, Steullet P, Steinmann M, Do KQ, Magistretti PJ, Halfon O, Cardinaux JR. TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity. Proc Natl Acad Sci USA. 2007 Mar;104(11):4700-5. CrossRef PubMed PubMedCentral
  11. Castillo PE. Presynaptic LTP and LTD of excitatory and inhibitory synapses. Cold Spring Harb Perspect Biol. 2012 Feb;4(2):a005728. CrossRef PubMed PubMedCentral
  12. Harney SC, Jane DE, Anwyl R. Extrasynaptic NR2D- containing NMDARs are recruited to the synapse during LTP of NMDAR-EPSCs. J Neurosci. 2008 Nov;28(45):11685-94. CrossRef PubMed PubMedCentral
  13. Yang Q, Zhu G, Liu D, Ju JG, Liao ZH, et al. Extrasynaptic NMDA receptor dependent long-term potentiation of hippocampal CA1 pyramidal neurons. Sci Rep. 2017 Jun;7(1):3045. CrossRef PubMed PubMedCentral
  14. De Roo M, Klauser P, Garcia PM, Poglia L, Muller D. Spine dynamics and synapse remodeling during LTP and memory processes. Prog Brain Res. 2008;169:199-207. CrossRef
  15. Iacono G, Benevento M, Dubos A, Herault Y, van Bokhoven H, et al. Integrated transcriptional analysis unveils the dynamics of cellular differentiation in the developing mouse hippocampus. Sci Rep. 2017 Dec;7(1):18073. CrossRef PubMed PubMedCentral
  16. Collingridge GL, Peineau S, Howland JG, Wang YT. Long-term depression in the CNS. Nat Rev Neurosci. 2010 Jul;11(7):459-73. CrossRef PubMed
  17. Bliss TV, Collingridge GL. Expression of NMDA receptor- dependent LTP in the hippocampus: bridging the divide. Mol Brain. 2013 Jan;6:5. CrossRef PubMed PubMedCentral
  18. Harris EW, Cotman CW. Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl D-aspartate antagonists. Neurosci Lett. 1986 Sep;70(1):132-7. CrossRef
  19. Nicoll RA, Schmitz D. Synaptic plasticity at hippo- campal mossy fibre synapses. Nat Rev Neurosci. 2005 Nov;6(11):863-76. CrossRef PubMed
  20. Alkadhi KA. NMDA receptor-independent LTP in mammalian nervous system. Prog Neurobiol. 2021 Jan 2:101986. CrossRef PubMed
  21. Li F, Tsien JZ. Memory and the NMDA receptors. N Engl J Med. 2009 Jul;361(3):302-3. CrossRef PubMed PubMedCentral
  22. Davies CH, Starkey SJ, Pozza MF, Collingridge GL. GABA autoreceptors regulate the induction of LTP. Nature. 1991 Feb 14;349(6310):609-11. CrossRef PubMed
  23. Hertle DN, Yeckel MF. Distribution of inositol-1,4,5- trisphosphate receptor isotypes and ryanodine receptor isotypes during maturation of the rat hippocampus. Neuroscience. 2007 Dec;150(3):625-38. CrossRef PubMed PubMedCentral
  24. Ringsevjen H, Umbach Hansen HM, Hussain S, Hvalby Ø, Jensen V, et al. Presynaptic increase in IP3 receptor type 1 concentration in the early phase of hippocampal synaptic plasticity. Brain Res. 2019 Mar;1706:125-34. CrossRef PubMed
  25. Taufiq AM, Fujii S, Yamazaki Y, Sasaki H, Kaneko K, et al. Involvement of IP3 receptors in LTP and LTD induction in guinea pig hippocampal CA1 neurons. Learn Mem. 2005 Nov-Dec;12(6):594-600. CrossRef PubMed PubMedCentral
  26. Kelleher RJ 3rd, Govindarajan A, Tonegawa S. Trans- lational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron. 2004 Sep;44(1):59-73. CrossRef PubMed
  27. Lushnikova IV, Nikonenko IR, Nikonenko OH, Skibo HH. Spatial distribution of synaptic vesicles in CA1 hippo- campal synapses under conditions of induced long-term potentiation in vitro. Fiziol Zh. 2008;54(1):35-44.
  28. Villacres EC, Wong ST, Chavkin C, Storm DR. Type I adenylyl cyclase mutant mice have impaired mossy fiber long-term potentiation. J Neurosci. 1998 May;18(9):3186-94. CrossRef PubMed PubMedCentral
  29. Evstratova A, Tóth K. Information processing and synaptic plasticity at hippocampal mossy fiber terminals. Front Cell Neurosci. 2014 Feb;8:28. CrossRef PubMed PubMedCentral
  30. Bortolotto ZA, Lauri S, Isaac JT, Collingridge GL. Kain- ate receptors and the induction of mossy fiber long-term potentiation. Philos Trans R Soc Lond B Biol Sci. 2003 Apr;358(1432):657-66 CrossRef PubMed PubMedCentral
  31. Lauri SE, Bortolotto ZA, Nistico R, Bleakman D, Ornstein PL, et al. A role for Ca2+ stores in kainate receptor-depen- dent synaptic facilitation and LTP at mossy fiber synapses in the hippocampus. Neuron. 2003 Jul;39(2):327-41. CrossRef
  32. Kapur A, Yeckel M, Johnston D. Hippocampal mossy fiber activity evokes Ca2+ release in CA3 pyramidal neurons via a metabotropic glutamate receptor pathway. Neurosci- ence. 2001;107(1):59-69. CrossRef
  33. Yeckel MF, Kapur A, Johnston D. Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism. Nat Neurosci. 1999 Jul;2(7):625-33. CrossRef PubMed PubMedCentral
  34. Barnes SJ, Opitz T, Merkens M, Kelly T, von der Brelie C, Krueppel R, Beck H. Stable mossy fiber long-term potentiation requires calcium influx at the granule cell soma, protein synthesis, and microtubule-dependent axo- nal transport. J Neurosci. 2010 Sep;30(39):12996-3004. CrossRef PubMed PubMedCentral
  35. Armstrong JN, Saganich MJ, Xu NJ, Henkemeyer M, Heinemann SF, Contractor A. B-ephrin reverse signaling is required for NMDA-independent long-term potentia- tion of mossy fibers in the hippocampus. J Neurosci. 2006 Mar;26(13):3474-81. CrossRef PubMed PubMedCentral
  36. Frey U, Morris RG. Synaptic tagging and long-term po- tentiation. Nature. 1997 Feb;385(6616):533-6. CrossRef PubMed
  37. Sajikumar S, Navakkode S, Sacktor TC, Frey JU. Synap- tic tagging and cross-tagging: the role of protein kinase Mzeta in maintaining long-term potentiation but not long- term depression. J Neurosci. 2005 Jun;25(24):5750-6. CrossRef PubMed PubMedCentral
  38. Martin KC, Kosik KS. Synaptic tagging - who's it? Nat Rev Neurosci. 2002 Oct;3(10):813-20. CrossRef PubMed
  39. Michmizos D, Koutsouraki E, Asprodini E, Baloyannis S. Synaptic plasticity: a unifying model to address some persisting questions. Int J Neurosci. 2011 Jun;121(6):289-304. CrossRef PubMed
  40. Redondo RL, Morris RG. Making memories last: the syn- aptic tagging and capture hypothesis. Nat Rev Neurosci. 2011 Jan;12(1):17-30. CrossRef PubMed
  41. Kanai Y, Dohmae N, Hirokawa N. Kinesin transports RNA: isolation and characterization of an RNA-trans- porting granule. Neuron. 2004 Aug;43(4):513-25. CrossRef PubMed
  42. Hu X, Viesselmann C, Nam S, Merriam E, Dent EW. Activity-dependent dynamic microtubule invasion of den- dritic spines. J Neurosci. 2008 Dec 3;28(49):13094-105. CrossRef PubMed PubMedCentral
  43. Steward O, Wallace CS, Lyford GL, Worley PF. Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites. Neuron. 1998 Oct;21(4):741-51. CrossRef
  44. Tao HW, Poo M. Retrograde signaling at central synapses. Proc Natl Acad Sci USA. 2001 Sep;98(20):11009-15. CrossRef PubMed PubMedCentral
  45. Regehr WG, Carey MR, Best AR. Activity-dependent regulation of synapses by retrograde messengers. Neuron. 2009 Jul 30;63(2):154-70. CrossRef PubMed PubMedCentral
  46. Contractor A, Rogers C, Maron C, Henkemeyer M, Swanson GT, Heinemann SF. Trans-synaptic Eph receptor-ephrin signaling in hippocampal mossy fiber LTP. Science. 2002 Jun;296(5574):1864-9. CrossRef PubMed
  47. Ohno-Shosaku T, Sawada S, Kano M. Heterosynaptic expression of depolarization-induced suppression of inhibition (DSI) in rat hippocampal cultures. Neurosci Res. 2000 Jan;36(1):67-71. CrossRef
  48. Ganguly K, Kiss L, Poo M. Enhancement of presynaptic neuronal excitability by correlated presynaptic and post- synaptic spiking. Nat Neurosci. 2000 Oct;3(10):1018-26. CrossRef PubMed
  49. Cash S, Zucker RS, Poo MM. Spread of synaptic depres- sion mediated by presynaptic cytoplasmic signaling. Science. 1996 May;272(5264):998-1001. CrossRef PubMed
  50. Lux HD, Veselovsky NS. Glutamate-produced long-term potentiation by selective challenge of presynaptic neu- rons in rat hippocampal cultures. Neurosci Lett. 1994 Sep;178(2):231-4. CrossRef
  51. Tucker KL, Meyer M, Barde YA. Neurotrophins are required for nerve growth during development. Nat Neurosci. 2001 Jan;4(1):29-37. CrossRef PubMed
  52. Hall AC, Lucas FR, Salinas PC. Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell. 2000 Mar;100(5):525-35. CrossRef
  53. Conner JM, Franks KM, Titterness AK, Russell K, Merrill DA, et al. NGF is essential for hippocampal plasticity and learning. J Neurosci. 2009 Sep;29(35):10883-9. CrossRef PubMed PubMedCentral
  54. DiStefano PS, Friedman B, Radziejewski C, Alexander C, Boland P, et al. The neurotrophins BDNF, NT-3, and NGF display distinct patterns of retrograde axonal transport in peripheral and central neurons. Neuron. 1992 May;8(5):983-93. CrossRef
  55. De Roo M, Klauser P, Garcia PM, Poglia L, Muller D. Spine dynamics and synapse remodeling during LTP and memory processes. Prog Brain Res. 2008;169:199-207. CrossRef
  56. Dunaevsky A, Tashiro A, Majewska A, Mason C, Yuste R. Developmental regulation of spine motility in the mammalian central nervous system. Proc Natl Acad Sci USA. 1999 Nov;96(23):13438-43. CrossRef PubMed PubMedCentral
  57. Neuhoff H, Roeper J, Schweizer M. Activity-dependent formation of perforated synapses in cultured hippocam- pal neurons. Eur J Neurosci. 1999 Dec;11(12):4241-50. CrossRef PubMed
  58. Toni N, Buchs PA, Nikonenko I, Povilaitite P, Parisi L, Muller D. Remodeling of synaptic membranes after induction of long-term potentiation. J Neurosci. 2001 Aug;21(16):6245-51. CrossRef PubMed PubMedCentral
  59. Knott GW, Holtmaat A, Wilbrecht L, Welker E, Svoboda K. Spine growth precedes synapse formation in the adult neocortex in vivo. Nat Neurosci. 2006 Sep;9(9):1117-24. Guedes-Dias P, Holzbaur ELF. Axonal transport: Driving synaptic function. Science. 2019 Oct;366(6462):eaaw9997. CrossRef PubMed
  60. Veselovsky NS, Engert F, Lux HD. Fast local superfusion technique. Pflügers Arch. 1996 Jun;432(2):351-4. CrossRef PubMed
  61. Brady ST. Molecular motors in the nervous system. Neu- ron. 1991 Oct;7(4):521-33. CrossRef
  62. Colley PA, Routtenberg A. Long-term potentiation as synaptic dialogue. Brain Res Brain Res Rev. 1993 Jan- Apr;18(1):115-22. CrossRef
  63. Malinow R, Tsien RW. Presynaptic enhancement shown by whole-cell recordings of long-term potentiation in hippocampal slices. Nature. 1990 Jul;346(6280):177-80. CrossRef PubMed
  64. Malinow R, Schulman H, Tsien RW. Inhibition of postsyn- aptic PKC or CaMKII blocks induction but not expression of LTP. Science. 1989 Aug;245(4920):862-6. CrossRef PubMed
  65. Goshima Y, Hida T, Gotoh T. Computational analysis of axonal transport: a novel assessment of neurotoxicity, neuronal development and functions. Int J Mol Sci. 2012;13(3):3414-30. CrossRef PubMed PubMedCentral
  66. Ye H, Kuruvilla R, Zweifel LS, Ginty DD. Evidence in support of signaling endosome-based retrograde survival of sympathetic neurons. Neuron. 2003 Jul;39(1):57-68. CrossRef
  67. Barnes SJ, Opitz T, Merkens M, Kelly T, von der Brelie C, Krueppel R, Beck H. Stable mossy fiber long-term potentiation requires calcium influx at the granule cell soma, protein synthesis, and microtu- bule-dependent axonal transport. J Neurosci. 2010 Sep;30(39):12996-3004. CrossRef PubMed PubMedCentral
  68. Hicks A, Davis S, Rodger J, Helme-Guizon A, Laroche S, Mallet J. Synapsin I and syntaxin 1B: key elements in the control of neurotransmitter release are regulated by neuronal activation and long-term potentiation in vivo. Neuroscience. 1997 Jul;79(2):329-40. CrossRef
  69. Lynch MA, Voss KL, Rodriguez J, Bliss TV. Increase in synaptic vesicle proteins accompanies long-term potentiation in the dentate gyrus. Neuroscience. 1994 May;60(1):1-5. CrossRef
  70. Cai Q, Pan PY, Sheng ZH. Syntabulin-kinesin-1 family member 5B-mediated axonal transport contributes to activity-dependent presynaptic assembly. J Neurosci. 2007 Jul;27(27):7284-96. CrossRef PubMed PubMedCentral
  71. Vickers CA, Wyllie DJ. Late-phase, protein synthesis- dependent long-term potentiation in hippocampal CA1 pyramidal neurons with destabilized microtubule net- works. Br J Pharmacol. 2007 Aug;151(7):1071-7. CrossRef PubMed PubMedCentral
  72. Vickers CA, Dickson KS, Wyllie DJ. Induction and main- tenance of late-phase long-term potentiation in isolated dendrites of rat hippocampal CA1 pyramidal neurones. J Physiol. 2005 Nov;568(Pt 3):803-13. CrossRef PubMed PubMedCentral
  73. Kelly MT, Yao Y, Sondhi R, Sacktor TC. Actin polym- erization regulates the synthesis of PKMzeta in LTP. Neuropharmacology. 2007 Jan;52(1):41-5. CrossRef PubMed
  74. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC. Storage of spatial information by the maintenance mechanism of LTP. Science. 2006 Aug;313(5790):1141-4. CrossRef PubMed

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2024.