Neurophysiological process - NMDA-dependent postsynaptic long-term potentiation in CA1 hippocampal neurons

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NMDA-dependent postsynaptic long-term potentiation in CA1 hippocampal neurons

long-term synaptic potentiation (LTP) is a cellular model of the activity-dependent enhancement of synaptic transmission in brain. Specific synapses employ different types of LTP mechanisms. NMDA receptor-dependent LTP in the CA1 region of the hippocampus remain the most extensively studied form of synaptic plasticity, and therefore is considered prototypic. [1], [2], [3].

LTP can be divided into two major stages. The early-LTP process involves such processes as activation of receptors by L-Glutamic acid, Ca('2+) current, by signaling mechanisms that provide additional activation of receptors, retrograde transport of agents to vesicles, and others. Expression of late-LTP genes is induced and new proteins are synthesized. Each stage can be additionally divided according to duration, time of initiation, and signaling [1], [3].

L-Glutamic acid released from presynaptic neurons activates receptor-channels on the surface of postsynaptic membrane. Activation of AMPA receptor leads to depolarization of the membrane. This allows overcoming the Mg(2+) block of NMDA receptor. Influx of Ca('2+) via these channels leads to activation of Calmodulin and CaMK II. The latter phosphorylates and activates AMPA receptor. Ca('2+) plays a critical role in the induction of LTP processes, possibly via participation in the induction of the retrograde agent transport [3], [4]. The nature of these agents however is yet unknown and is being actively debated. Possible candidates are Arachidonic acid, NO, NO, and BDNF [1], [2], [5], [6]. mGluR1 is also activated by L-Glutamic acid. It transforms G-protein alpha-q and induces Phospholipase C beta (PLC-beta) activation with subsequent release of IP3 and 1,2-Diacyglycerol . IP3 binding to IP3 receptor leads to Ca('2+) transport from endoplasmic reticulum to cytoplasm. 1,2-Diacyglycerol and Ca('2+) participate in activation of the Protein kinase C (PKC) [3]. PKC, probably, PKC-alpha in particular [7], phosphorylates NMDA receptor subunits. This reduces Mg(2+) block of NMDA receptor and leads to its activation [3], [8]. Calmodulin activates adenylate cyclases, which produce Cyclic AMP, leading to activation of PKA-cat (cAMP-dependent). The latter phosphorylates and activates AMPA receptor [4].

PKA-cat (cAMP-dependent), a common activator of CREB1, possibly takes part in early and late-LTP signaling processes [9], [10], [11]. NMDA-induced PKA-cat (cAMP-dependent) participates in translocation of ERK1/2 into the nucleus [12]. ERK1/2 then activates MNK1/ eIF4E, and thereby induces protein synthesis [11], [13]. Cyclic AMP affects LTP stability by activating cAMP-GEFI that subsequently activates ERK1/2[14]. This pathway is possibly accomplished via activation of RAP-1A and B-Raf [15]. But traditionally, activation of RAP-1A is linked to a process of long-term depression, because it activates p38 MAPK and participates in removal of AMPA receptor from the cell membrane [16], [17].

NMDA receptor induces a number of pathways of ERK1/2 activation. NMDA receptor activates Ras protein-specific guanine nucleotide-releasing factor (RASGRF) signaling to ERK1/2 activation. NR2A binds RASGRF2 [18] and NR2B binds RASGRF1 [19]. Data on biological effects of NR2A and NR2B signaling pathways are controversial. The effects possibly depend on switching of signaling from activation of ERK1/2 to p38 MAPK and thus leading to LTP or LTD. Some reports indicate that NR2A and NR2B both induce LTP [17], [19], [20]. Others show that NR2A induces LTP and NR2B induces LTD [18], [21] in CA1 region of the hippocampus, depending on the stage of development of the organism. RASGRF influences ERK1/2/ CREB1 activation via H-Ras/ c-Raf-1/ MEK1/2 pathway [22].

NMDA can activate ERK1/2 via CaMK II [16] and Shc/ GRB2/ SOS (the latter process was studied in other brain parts [22], at least in neonatal brain).

ERK1/2 participates in the insertion of AMPA receptor into the membrane and thus in the maintenance of the LTP [16], [17], [21].

ERK1/2 and CaMK II and CaMK IV directly phosphorylate CREB1 [23], [24].

CREB1 is the most important transcription regulator of genes involed in LTP. It is activated directly by CaMK II and CaMK IV [23], [24] and ERK1/2 via p90Rsk [12]. It can activate transcription of other transcription factors, e.g., c-Fos [24], or proteins important for development of LTP, e.g., BDNF. It can also play a role of a retrograde agent, and to participate in modulation of the actin network in neuronal spines [25].

Ca('2+) concentration elevated during LTP induces activation of eNOS [26], [27]. Production of NO leads to activation of the soluble Guanylate Cyclase 1, soluble and to Cyclic GMP synthesis. Cyclic GMP participates in activation of Protein kinase G, e.g., Protein kinase G 2, that in turn activates Ryanodine receptors and elevates Ca('2+) level [28], [29], [30]. Ryanodine receptor 2 is one of possible representatives of such receptors that participate of long-term memory processes [31]. Ryanodine receptor 3 is possibly important for LTP formation in CA1 However, mechanisms of its activation by Protein kinase G is still not clear [32]. Protein kinase G also takes part in ERK1/2 activation of signaling [27]

NMDA in CA1 also influences Phosphoinositide-3-kinase (PI3K) signaling, leading to late LTP. Activation of PI3K is induced by Ras (probably, H-Ras). PI3K reg class IA (p85-alpha)/ PI3K cat class IA (p110-alpha) complex subsequently associates with GluR1 and GluR2, the subunits of AMPA receptor, and promotes their insertion into the membrane [33]. PI3K signaling that leads to activation of AKT(PKB) also promotes GluR1 insertion to membrane [34] and participates in activation of mTOR via p70 S6 kinase1, leading to dendrite-wide translation; synaptic-specific activation is likely to be necessary for long-term synaptic potentiation [35].



Objects list:

1,2-Diacyglycerol 1,2-Diacyglycerol Compound group
AKT(PKB) AKT(PKB) Protein group
AMPA receptor AMPA receptor Complex
B-Raf Serine/threonine-protein kinase B-raf
BDNF Brain-derived neurotrophic factor
CREB1 Cyclic AMP-responsive element-binding protein 1
Ca('2+) Chemical IUPAC name calcium(+2) cation
Ca('2+) Chemical IUPAC name calcium(+2) cation
Ca('2+) Chemical IUPAC name calcium(+2) cation
CaMK II CaMK II Complex
CaMK IV Calcium/calmodulin-dependent protein kinase type IV
Calmodulin Calmodulin
Cyclic AMP Chemical IUPAC name (1S,6R,8R,9R)-8-(6-amino-8-bromopurin-9-yl)-3-hydroxy-3-oxo-2,4,7-trioxa-35-phosphabicyclo[4.3.0]nonan-9-ol
Cyclic GMP Chemical IUPAC name Guanosine 3',5'-cyclic phosphate
ERK1/2 Erk 1/2 Protein group
GRB2 Growth factor receptor-bound protein 2
GluR1 Glutamate receptor 1
GluR2 Glutamate receptor 2
Guanylate Cyclase 1, soluble soluble Guanylate Cyclase Group of complexes
H-Ras GTPase HRas
IP3 Chemical IUPAC name [(1R,2S,3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-diphosphonooxycyclohexyl] dihydrogen phosphate
IP3 receptor A family of receptors for the second messenger inositol 1,4,5-trisphosphate (IP3) Protein group
L-Glutamic acid Chemical IUPAC name (2S)-2-Aminopentanedioic acid
MEK1/2 MEK1/2 Protein group
MNK1 MAP kinase-interacting serine/threonine-protein kinase 1
NMDA receptor NMDA receptor Group of complexes
NO Chemical IUPAC name Nitric oxide
NR2A Glutamate [NMDA] receptor subunit epsilon-1
NR2B Glutamate [NMDA] receptor subunit epsilon-2
PI3K cat class IA (p110-alpha) Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
PI3K reg class IA (p85-alpha) Phosphatidylinositol 3-kinase regulatory subunit alpha
PKA-cat (cAMP-dependent) Protein kinase, cAMP-dependent, catalytic Protein group
PKC-alpha Protein kinase C alpha type
Protein kinase G Protein kinase G Protein group
Protein kinase G 2 cGMP-dependent protein kinase 2
RAP-1A Ras-related protein Rap-1A
RASGRF1 Ras-specific guanine nucleotide-releasing factor 1
RASGRF2 Ras-specific guanine nucleotide-releasing factor 2
Ryanodine receptor 2 Ryanodine receptor 2
Ryanodine receptor 3 Ryanodine receptor 3
SOS SOS Protein group
Shc SHC-transforming protein 1
c-Fos Proto-oncogene c-Fos
c-Raf-1 RAF proto-oncogene serine/threonine-protein kinase
cAMP-GEFI Rap guanine nucleotide exchange factor 3
eIF4E Eukaryotic translation initiation factor 4E
eNOS Nitric oxide synthase, endothelial
mGluR1 Metabotropic glutamate receptor 1
mTOR Serine/threonine-protein kinase mTOR
p70 S6 kinase1 Ribosomal protein S6 kinase beta-1
p90Rsk p90 ribosomal S6 kinases Protein group

References:

  1. Malenka RC, Bear MF
    LTP and LTD: an embarrassment of riches. Neuron 2004 Sep 30;44(1):5-21
  2. Miyamoto E
    Molecular mechanism of neuronal plasticity: induction and maintenance of long-term potentiation in the hippocampus. Journal of pharmacological sciences 2006;100(5):433-42
  3. Reymann KG, Frey JU
    The late maintenance of hippocampal LTP: requirements, phases, 'synaptic tagging', 'late-associativity' and implications. Neuropharmacology 2007 Jan;52(1):24-40
  4. Xia Z, Storm DR
    The role of calmodulin as a signal integrator for synaptic plasticity. Nature reviews. Neuroscience 2005 Apr;6(4):267-76
  5. Medina JH, Izquierdo I
    Retrograde messengers, long-term potentiation and memory. Brain research. Brain research reviews 1995 Sep;21(2):185-94
  6. Tao HW, Poo M
    Retrograde signaling at central synapses. Proceedings of the National Academy of Sciences of the United States of America 2001 Sep 25;98(20):11009-15
  7. Moriguchi S, Han F, Nakagawasai O, Tadano T, Fukunaga K
    Decreased calcium/calmodulin-dependent protein kinase II and protein kinase C activities mediate impairment of hippocampal long-term potentiation in the olfactory bulbectomized mice. Journal of neurochemistry 2006 Apr;97(1):22-9
  8. Chen L, Huang LY
    Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature 1992 Apr 9;356(6369):521-3
  9. Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R
    Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 1997 Mar 7;88(5):615-26
  10. Duffy SN, Nguyen PV
    Postsynaptic application of a peptide inhibitor of cAMP-dependent protein kinase blocks expression of long-lasting synaptic potentiation in hippocampal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 2003 Feb 15;23(4):1142-50
  11. Banko JL, Hou L, Klann E
    NMDA receptor activation results in PKA- and ERK-dependent Mnk1 activation and increased eIF4E phosphorylation in hippocampal area CA1. Journal of neurochemistry 2004 Oct;91(2):462-70
  12. Impey S, Obrietan K, Wong ST, Poser S, Yano S, Wayman G, Deloulme JC, Chan G, Storm DR
    Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 1998 Oct;21(4):869-83
  13. Klann E, Dever TE
    Biochemical mechanisms for translational regulation in synaptic plasticity. Nature reviews. Neuroscience 2004 Dec;5(12):931-42
  14. Gelinas JN, Banko JL, Peters MM, Klann E, Weeber EJ, Nguyen PV
    Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus. Learning & memory (Cold Spring Harbor, N.Y.) 2008 Jun;15(6):403-11
  15. de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A, Bos JL
    Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 1998 Dec 3;396(6710):474-7
  16. Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R
    Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 2002 Aug 23;110(4):443-55
  17. Zhu Y, Pak D, Qin Y, McCormack SG, Kim MJ, Baumgart JP, Velamoor V, Auberson YP, Osten P, van Aelst L, Sheng M, Zhu JJ
    Rap2-JNK removes synaptic AMPA receptors during depotentiation. Neuron 2005 Jun 16;46(6):905-16
  18. Li S, Tian X, Hartley DM, Feig LA
    Distinct roles for Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in the induction of long-term potentiation and long-term depression. The Journal of neuroscience : the official journal of the Society for Neuroscience 2006 Feb 8;26(6):1721-9
  19. Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R, Pellegrino C, Ben-Ari Y, Clapham DE, Medina I
    The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron 2003 Nov 13;40(4):775-84
  20. Bartlett TE, Bannister NJ, Collett VJ, Dargan SL, Massey PV, Bortolotto ZA, Fitzjohn SM, Bashir ZI, Collingridge GL, Lodge D
    Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus. Neuropharmacology 2007 Jan;52(1):60-70
  21. Kim MJ, Dunah AW, Wang YT, Sheng M
    Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron 2005 Jun 2;46(5):745-60
  22. Tian X, Gotoh T, Tsuji K, Lo EH, Huang S, Feig LA
    Developmentally regulated role for Ras-GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB. The EMBO journal 2004 Apr 7;23(7):1567-75
  23. Wu GY, Deisseroth K, Tsien RW
    Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proceedings of the National Academy of Sciences of the United States of America 2001 Feb 27;98(5):2808-13
  24. Kasahara J, Fukunaga K, Miyamoto E
    Activation of calcium/calmodulin-dependent protein kinase IV in long term potentiation in the rat hippocampal CA1 region. The Journal of biological chemistry 2001 Jun 29;276(26):24044-50
  25. Rex CS, Lin CY, Kramár EA, Chen LY, Gall CM, Lynch G
    Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 2007 Mar 14;27(11):3017-29
  26. Haley JE, Schaible E, Pavlidis P, Murdock A, Madison DV
    Basal and apical synapses of CA1 pyramidal cells employ different LTP induction mechanisms. Learning & memory (Cold Spring Harbor, N.Y.) 1996 Nov-Dec;3(4):289-95
  27. Chien WL, Liang KC, Teng CM, Kuo SC, Lee FY, Fu WM
    Enhancement of long-term potentiation by a potent nitric oxide-guanylyl cyclase activator, 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole. Molecular pharmacology 2003 Jun;63(6):1322-8
  28. Lu YF, Hawkins RD
    Ryanodine receptors contribute to cGMP-induced late-phase LTP and CREB phosphorylation in the hippocampus. Journal of neurophysiology 2002 Sep;88(3):1270-8
  29. Monfort P, Muñoz MD, Kosenko E, Felipo V
    Long-term potentiation in hippocampus involves sequential activation of soluble guanylate cyclase, cGMP-dependent protein kinase, and cGMP-degrading phosphodiesterase. The Journal of neuroscience : the official journal of the Society for Neuroscience 2002 Dec 1;22(23):10116-22
  30. Wu H, Zhou Y, Xiong ZQ
    Transducer of regulated CREB and late phase long-term synaptic potentiation. The FEBS journal 2007 Jul;274(13):3218-23
  31. Cavallaro S, Meiri N, Yi CL, Musco S, Ma W, Goldberg J, Alkon DL
    Late memory-related genes in the hippocampus revealed by RNA fingerprinting. Proceedings of the National Academy of Sciences of the United States of America 1997 Sep 2;94(18):9669-73
  32. Balschun D, Wolfer DP, Bertocchini F, Barone V, Conti A, Zuschratter W, Missiaen L, Lipp HP, Frey JU, Sorrentino V
    Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning. The EMBO journal 1999 Oct 1;18(19):5264-73
  33. Man HY, Wang Q, Lu WY, Ju W, Ahmadian G, Liu L, D'Souza S, Wong TP, Taghibiglou C, Lu J, Becker LE, Pei L, Liu F, Wymann MP, MacDonald JF, Wang YT
    Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons. Neuron 2003 May 22;38(4):611-24
  34. Qin Y, Zhu Y, Baumgart JP, Stornetta RL, Seidenman K, Mack V, van Aelst L, Zhu JJ
    State-dependent Ras signaling and AMPA receptor trafficking. Genes & development 2005 Sep 1;19(17):2000-15
  35. Cammalleri M, Lütjens R, Berton F, King AR, Simpson C, Francesconi W, Sanna PP
    Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1. Proceedings of the National Academy of Sciences of the United States of America 2003 Nov 25;100(24):14368-73

  1. Malenka RC, Bear MF
    LTP and LTD: an embarrassment of riches. Neuron 2004 Sep 30;44(1):5-21
  2. Miyamoto E
    Molecular mechanism of neuronal plasticity: induction and maintenance of long-term potentiation in the hippocampus. Journal of pharmacological sciences 2006;100(5):433-42
  3. Reymann KG, Frey JU
    The late maintenance of hippocampal LTP: requirements, phases, 'synaptic tagging', 'late-associativity' and implications. Neuropharmacology 2007 Jan;52(1):24-40
  4. Xia Z, Storm DR
    The role of calmodulin as a signal integrator for synaptic plasticity. Nature reviews. Neuroscience 2005 Apr;6(4):267-76
  5. Medina JH, Izquierdo I
    Retrograde messengers, long-term potentiation and memory. Brain research. Brain research reviews 1995 Sep;21(2):185-94
  6. Tao HW, Poo M
    Retrograde signaling at central synapses. Proceedings of the National Academy of Sciences of the United States of America 2001 Sep 25;98(20):11009-15
  7. Moriguchi S, Han F, Nakagawasai O, Tadano T, Fukunaga K
    Decreased calcium/calmodulin-dependent protein kinase II and protein kinase C activities mediate impairment of hippocampal long-term potentiation in the olfactory bulbectomized mice. Journal of neurochemistry 2006 Apr;97(1):22-9
  8. Chen L, Huang LY
    Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature 1992 Apr 9;356(6369):521-3
  9. Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R
    Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 1997 Mar 7;88(5):615-26
  10. Duffy SN, Nguyen PV
    Postsynaptic application of a peptide inhibitor of cAMP-dependent protein kinase blocks expression of long-lasting synaptic potentiation in hippocampal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 2003 Feb 15;23(4):1142-50
  11. Banko JL, Hou L, Klann E
    NMDA receptor activation results in PKA- and ERK-dependent Mnk1 activation and increased eIF4E phosphorylation in hippocampal area CA1. Journal of neurochemistry 2004 Oct;91(2):462-70
  12. Impey S, Obrietan K, Wong ST, Poser S, Yano S, Wayman G, Deloulme JC, Chan G, Storm DR
    Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 1998 Oct;21(4):869-83
  13. Klann E, Dever TE
    Biochemical mechanisms for translational regulation in synaptic plasticity. Nature reviews. Neuroscience 2004 Dec;5(12):931-42
  14. Gelinas JN, Banko JL, Peters MM, Klann E, Weeber EJ, Nguyen PV
    Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus. Learning & memory (Cold Spring Harbor, N.Y.) 2008 Jun;15(6):403-11
  15. de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A, Bos JL
    Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 1998 Dec 3;396(6710):474-7
  16. Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R
    Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 2002 Aug 23;110(4):443-55
  17. Zhu Y, Pak D, Qin Y, McCormack SG, Kim MJ, Baumgart JP, Velamoor V, Auberson YP, Osten P, van Aelst L, Sheng M, Zhu JJ
    Rap2-JNK removes synaptic AMPA receptors during depotentiation. Neuron 2005 Jun 16;46(6):905-16
  18. Li S, Tian X, Hartley DM, Feig LA
    Distinct roles for Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in the induction of long-term potentiation and long-term depression. The Journal of neuroscience : the official journal of the Society for Neuroscience 2006 Feb 8;26(6):1721-9
  19. Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R, Pellegrino C, Ben-Ari Y, Clapham DE, Medina I
    The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron 2003 Nov 13;40(4):775-84
  20. Bartlett TE, Bannister NJ, Collett VJ, Dargan SL, Massey PV, Bortolotto ZA, Fitzjohn SM, Bashir ZI, Collingridge GL, Lodge D
    Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus. Neuropharmacology 2007 Jan;52(1):60-70
  21. Kim MJ, Dunah AW, Wang YT, Sheng M
    Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron 2005 Jun 2;46(5):745-60
  22. Tian X, Gotoh T, Tsuji K, Lo EH, Huang S, Feig LA
    Developmentally regulated role for Ras-GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB. The EMBO journal 2004 Apr 7;23(7):1567-75
  23. Wu GY, Deisseroth K, Tsien RW
    Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proceedings of the National Academy of Sciences of the United States of America 2001 Feb 27;98(5):2808-13
  24. Kasahara J, Fukunaga K, Miyamoto E
    Activation of calcium/calmodulin-dependent protein kinase IV in long term potentiation in the rat hippocampal CA1 region. The Journal of biological chemistry 2001 Jun 29;276(26):24044-50
  25. Rex CS, Lin CY, Kramár EA, Chen LY, Gall CM, Lynch G
    Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 2007 Mar 14;27(11):3017-29
  26. Haley JE, Schaible E, Pavlidis P, Murdock A, Madison DV
    Basal and apical synapses of CA1 pyramidal cells employ different LTP induction mechanisms. Learning & memory (Cold Spring Harbor, N.Y.) 1996 Nov-Dec;3(4):289-95
  27. Chien WL, Liang KC, Teng CM, Kuo SC, Lee FY, Fu WM
    Enhancement of long-term potentiation by a potent nitric oxide-guanylyl cyclase activator, 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole. Molecular pharmacology 2003 Jun;63(6):1322-8
  28. Lu YF, Hawkins RD
    Ryanodine receptors contribute to cGMP-induced late-phase LTP and CREB phosphorylation in the hippocampus. Journal of neurophysiology 2002 Sep;88(3):1270-8
  29. Monfort P, Muñoz MD, Kosenko E, Felipo V
    Long-term potentiation in hippocampus involves sequential activation of soluble guanylate cyclase, cGMP-dependent protein kinase, and cGMP-degrading phosphodiesterase. The Journal of neuroscience : the official journal of the Society for Neuroscience 2002 Dec 1;22(23):10116-22
  30. Wu H, Zhou Y, Xiong ZQ
    Transducer of regulated CREB and late phase long-term synaptic potentiation. The FEBS journal 2007 Jul;274(13):3218-23
  31. Cavallaro S, Meiri N, Yi CL, Musco S, Ma W, Goldberg J, Alkon DL
    Late memory-related genes in the hippocampus revealed by RNA fingerprinting. Proceedings of the National Academy of Sciences of the United States of America 1997 Sep 2;94(18):9669-73
  32. Balschun D, Wolfer DP, Bertocchini F, Barone V, Conti A, Zuschratter W, Missiaen L, Lipp HP, Frey JU, Sorrentino V
    Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning. The EMBO journal 1999 Oct 1;18(19):5264-73
  33. Man HY, Wang Q, Lu WY, Ju W, Ahmadian G, Liu L, D'Souza S, Wong TP, Taghibiglou C, Lu J, Becker LE, Pei L, Liu F, Wymann MP, MacDonald JF, Wang YT
    Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons. Neuron 2003 May 22;38(4):611-24
  34. Qin Y, Zhu Y, Baumgart JP, Stornetta RL, Seidenman K, Mack V, van Aelst L, Zhu JJ
    State-dependent Ras signaling and AMPA receptor trafficking. Genes & development 2005 Sep 1;19(17):2000-15
  35. Cammalleri M, Lütjens R, Berton F, King AR, Simpson C, Francesconi W, Sanna PP
    Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1. Proceedings of the National Academy of Sciences of the United States of America 2003 Nov 25;100(24):14368-73

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