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. , , .
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 , .
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 , . The nature of these agents however is yet unknown and is being actively debated. Possible candidates are Arachidonic acid, NO, NO, and BDNF , , , . 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) . PKC, probably, PKC-alpha in particular , phosphorylates NMDA receptor subunits. This reduces Mg(2+) block of NMDA receptor and leads to its activation , . Calmodulin activates adenylate cyclases, which produce Cyclic AMP, leading to activation of PKA-cat (cAMP-dependent). The latter phosphorylates and activates AMPA receptor .
PKA-cat (cAMP-dependent), a common activator of CREB1, possibly takes part in early and late-LTP signaling processes , , . NMDA-induced PKA-cat (cAMP-dependent) participates in translocation of ERK1/2 into the nucleus . ERK1/2 then activates MNK1/ eIF4E, and thereby induces protein synthesis , . Cyclic AMP affects LTP stability by activating cAMP-GEFI that subsequently activates ERK1/2. This pathway is possibly accomplished via activation of RAP-1A and B-Raf . 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 , .
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  and NR2B binds RASGRF1 . 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 , , . Others show that NR2A induces LTP and NR2B induces LTD ,  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 .
NMDA can activate ERK1/2 via CaMK II  and Shc/ GRB2/ SOS (the latter process was studied in other brain parts , 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 , , .
ERK1/2 and CaMK II and CaMK IV directly phosphorylate CREB1 , .
CREB1 is the most important transcription regulator of genes involed in LTP. It is activated directly by CaMK II and CaMK IV ,  and ERK1/2 via p90Rsk . It can activate transcription of other transcription factors, e.g., c-Fos , 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 .
Ca("2+) concentration elevated during LTP induces activation of eNOS , . 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 , , . Ryanodine receptor 2 is one of possible representatives of such receptors that participate of long-term memory processes . Ryanodine receptor 3 is possibly important for LTP formation in CA1 However, mechanisms of its activation by Protein kinase G is still not clear . Protein kinase G also takes part in ERK1/2 activation of signaling 
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 . PI3K signaling that leads to activation of AKT(PKB) also promotes GluR1 insertion to membrane  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 .
| 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 |
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