Skip to main content

Basic roles of key molecules connected with NMDAR signaling pathway on regulating learning and memory and synaptic plasticity


With key roles in essential brain functions ranging from the long-term potentiation (LTP) to synaptic plasticity, the N-methyl-D-aspartic acid receptor (NMDAR) can be considered as one of the fundamental glutamate receptors in the central nervous system. The role of NMDA R was first identified in synaptic plasticity and has been extensively studied. Some molecules, such as Ca2+, postsynaptic density 95 (PSD-95), calcium/calmodulin-dependent protein kinase II (CaMK II), protein kinase A (PKA), mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB), are of special importance in learning and memory. This review mainly focused on the new research of key molecules connected with learning and memory, which played important roles in the NMDAR signaling pathway.


Glutamate, one of the most common neurotransmitters in the central nervous system, has been found to regulate various memory-connected activities. Glutamate receptors, as the most important excitatory amino acid receptors in the mammalian central nervous system, have been confirmed to be associated with the formation of synapses, the release and transport of neurotransmitters, synaptic plasticity and learning and memory [1]. N-methyl-D-aspartic acid receptor (NMDAR) is an important glutamate receptor, which has been proven to be closely related to long-term potentiation (LTP), learning and memory, the development of neural plasticity, hypoxic-ischemic injuries and some neurodegenerative diseases [2]. The role of NMDAR in regulating learning and memory has been confirmed by different experimental methods, such as gene knockout or overexpression, electrophysiological techniques, agonists, and antagonists [35]. Some key molecules of NMDAR signaling pathway in postsynaptic neurons play important roles in regulating learning and memory, which can be summarized as the following processes. Firstly, the release of presynaptic glutamate can activate the postsynaptic NMDAR, leading to the removal of magnesium ions and the influx of calcium. Then, the calcium could bind to the calmodulin to activate the calmodulin-dependent protein kinase and protein kinases A and C, which are the basis for activating mitogen-activated protein kinase (MAPK). Furthermore, the activated MAPK can be transported to the nucleus and activate cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB), resulting in the expression of downstream genes, such as tissue-type plasminogen activator (tPA) and brain-derived neurotrophic factor (BDNF), among others. Finally, the new synthetic substances can cause the growth of original synapses and the formation of new synapses (Fig. 1). The aim of this review is to discuss the important processes connected with NMDAR dependent learning and memory.

Fig. 1
figure 1

The regulation of molecules in the NMDAR signaling pathway on learning and memory. The release of presynaptic glutamate can activate postsynaptic NMDAR, leading to the removal of magnesium ions and the influx of calcium. The calcium could bind to the calmodulin to activate the calmodulin-dependent PKA and PKC, which are the basis for the activation of MAPK. Furthermore, the activated MAPK can be transported into the nucleus and activate CREB, resulting the expression of downstream genes, such as tPA and BDNF, among others. Finally, the new synthetic substances can cause the growth of original synapses and the formation of new synapses, which are the basis for synaptic plasticity and learning and memory

Activation of NMDARs and the influx of calcium

NMDARs, voltage- and ligand-gated channels, are found throughout the central nervous system and contribute to synaptic plasticity and intracellular Ca2+ transients. NMDARs can be activated by the binding of presynaptic glutamate as well as through postsynaptic depolarization. At the rest potential, when the presynaptic membrane is activated, many neurotransmitters are released into the synaptic cleft, including glutamate. The released glutamate can bind to both α-postsynaptic amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and NMDAR. Under this condition, barely any ions can flow through the NMDARs because of the negative resting potential and the Mg2+ blocking site. However, the Na+ and K+ can pass through AMPARs, resulting in the depolarization of the postsynaptic membrane. Furthermore, a large depolarized current would cause the Mg2+ to become unbound from NMDAR, leading to the open state of the NMDAR channel and the subsequent influx of Ca2+, which is one of the triggering factors for the LTP induction and maintenance [6]. Sanna et al. [7] found that the transient use of glutamate or NMDA at the dendrites of pyramidal cells could increase the intracellular Ca2+ concentration, however this reaction can be inhibited by the NMDAR antagonist AP-5 or extracellular Mg2+. The phosphorylation status of NMDAR is an important factor that reflects the activation status of NMDAR and determines the permeability of calcium ions. In other words, their permeability is enhanced by phosphorylation, whereas dephosphorylation decreases calcium permeability [8, 9].

In addition to the NMDAR channel, the voltage-gated calcium channel (VGCC), metabotropic glutamate receptor (mGluR) and cytosolic calcium stores, including the endoplasmic reticulum, are other important ways for the increase of intracellular calcium ions [10, 11]. The increased Ca2+ in postsynaptic neuron contributes to the rearrangement of cell scaffolding proteins, the increase of postsynaptic area and the decrease of resistance during synaptic transmission, leading to the formation of LTP [12, 13]. Moreover, the calcium, as an important intracellular second messenger, can activate several important protein kinases, such as protein kinase A (PKA), calcium/calmodulin-dependent protein kinase II (CaMK II), and MAPK, among others, resulting in the start of a downstream signal pathway.

Bridging roles of PSD-95 in postsynaptic plasticity

Postsynaptic density, located at the cytoplasmic membrane, is a large semicircular area of high electronic density. The main components of postsynaptic density are types of receptors, including CaMK II and postsynaptic density 95 (PSD-95), among others. One study found that the CaMK II and PSD-95 were mainly bound to the NR2B subunits [14]. Another study found that hippocampal synaptic plasticity was related to the competitive binding of the C-terminus of NR2A to either CaMK II or PSD-95 [15].

PSD-95, an important scaffold protein in the postsynaptic membrane, serves as a bridge between NMDARs and downstream signal molecules and plays roles in the maturation of neurons and the development of synapses. In addition, PSD-95 binds various regulatory proteins, including Src, Pyk2, SynGAP, and nNOS and may recruit signaling proteins to NMDARs [16]. Studies have found that the overexpression of PSD-95 in hippocampal neurons can drive the maturation of glutamatergic synapses as well as enhance postsynaptic clustering, the activity of glutamate receptors and the maturation of presynaptic terminal, thus indicating its roles in synapse stabilization and plasticity [17, 18]. In PSDs, NR2A and NR2B subunits directly interact with PSD-95 and other members of the membrane-associated guanylate kinase family. Studies found that the PSD-95-like membrane-associated guanylate kinases (PSD-MAGUKs) specifically played roles in clustering signaling molecules near NMDAR. The ligand binding-deficient PSD-95 cDNA knockin mice presented with markedly abnormal anxiety-like behavior, impaired spatial reference and working memory, and impaired remote memory and pattern separation in fear conditioning tests [19]. TrkB, a BDNF receptor, regulates the postsynaptic localization of PSD-95 through the following three downstream pathways: phosphatidylinositol 3-kinase (PI3K), phospholipase Cγ (PLCγ) and MAPK/extracellular signal-regulated kinases (MAPK/ERK) [20].

Autophosphorylation of CaMK II and its role in learning and memory

CaMK II, a serine/threonine kinase, is activated during the induction of LTP through the calcium ion influx through NMDAR [21]. CaMK II has more than 30 types of subtypes and multiple substrates. CaMK II is likely a mediator of primary importance in linking transient calcium signals to neuronal plasticity. When NMDAR is activated, calcium ions are transported through the receptor channel and then bind to calmodulin (CaM). The Ca2+/CaM complex can then bind to the contiguous sequences and consequently displace the Ca2+ from the CaM catalytic domain, leading the autophosphorylation of CaMK II at Thr286 [22]. The activated CaMK II can then move to the PSD and subsequently induce LTP. Studies found that the synaptic strength was stored stably through the combined actions of the CaMK II/NMDAR complex and N-cadherin dimers, which have redundant storage that could provide informational stability in a manner analogous to base-pairing in DNA [23]. In the maintenance of LTP, the CaMK II can bind to a number of postsynaptic density proteins, such as α-actinin, PSD-95, synaptic adhesion molecule, and densin-180. The activated CaMK II can also cause the activation of microtubule-associated protein 2 (MAP2) and neurofilament L, indicating the close relationship of CaMK II and structural synaptic plasticity [24]. The synaptic scaffolding protein CaM associated serine kinase (CASK) is also important for learning and memory, as mutations in CASK result in intellectual disability and neurological defects in humans. Previous research has found that the expression of human CASK in Drosophila rescued the effect of CASK deletion on the activity state of CaMK II, suggesting that human CASK may also regulate CaMK II autophosphorylation in neuronal growth, calcium signaling, and learning [25].

To test the role of CaMK II autophosphorylation in synaptic plasticity, research studies were conducted with transgenic mice that express CaMK II-Asp-286 instead of CaMK II-Thr-286 [26]. Although the calcium-independent activity increased two times, the hippocampal LTP induction at CA1 region was inhibited and the spatial memory was impaired when the mice were subjected to a Morris water maze [27]. Above all, CaMK II plays a key role during LTP induction by enhancing alternations in synaptic efficiency [28].

The production of cAMP and activation of PKA and MAPK

The increase of calcium ions in postsynaptic neurons can activate adenylyl cyclase, leading to the expression of cAMP and the activation of PKA. The increased cAMP could cause MAPK to be transported to the nucleus.

PKA plays a role in the cytoplasm, which can phosphorylate different substrates, for example, GluR1 of AMPAR, which can counteract protein phosphatase 1 (PP1), facilitate LTP induction and impact learning and memory [29]. Experiments showed that the incidence of LTP induction could be decreased by the antagonist of PKA, indicating the PKA was a key molecule for LTP [30]. The activation of PKA or the inhibition of PP1 can increase the NMDAR dependent postsynaptic potentials [31]. Researchers generated transgenic mice that express R(AB), an inhibitory form of the regulatory subunit of PKA, finding deficits in long-term memory and confirming the critical role of PKA in the consolidation of long-term memory [32].

There are four subtypes of MAPK, namely extracellular signal-regulated protein kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK), c-jun N-terminal kinase (JNK, also known as stress-activated MAPK) and ERK5. After the phosphorylation of MAPK, MAPK can enter the nucleus and phosphorylate nuclear transcription factors, leading to the expression of downstream target genes and the synthesis of new proteins [33, 34]. MAPK is indispensable to generating hippocampal LTP. The extracellular signal-regulated kinase 1/2 (ERK1/2) is a best characterized subclass of MAPKs; its phosphorylation was resistant to the inhibition of protein kinase C, p38 MAPK, cyclin-dependent kinase 5, and receptor tyrosine kinase (epidermal growth factor receptors) or non-receptor tyrosine kinases (including Src) by their selective inhibitors [35]. One research study reported that PD 098059, a selective inhibitor of the MAPK cascade, blocked MAPK activation in response to the direct stimulation of NMDAR as well as to LTP-inducing stimuli, which provided evidence of its role in the MAPK cascade, specifically in the activity-dependent modification of synaptic connections between neurons in the adult mammalian nervous system [36].

In addition to protein kinase, protein phosphatase also regulates LTP and memory. However, unlike the PKA and MAPK cascades, the protein phosphatase 1 and calcineurin are negative regulation factors for LTP formation. Researchers found that the physiological importance of PP1 and calcineurin constrained LTP and memory [3739].

The phosphorylation of CREB and its regulatory roles

CREB, one of the earliest confirmed and phosphorylation regulated transcription factors, is expressed in nearly all cells of the brain and is localized in the nucleus. CREB regulates the gene transcription of cAMP at the promoter region and a large number of downstream target genes induced by a variety of signaling molecules. The phosphorylation of CREB affects the expression of many neuronal genes and proteins, regulating the entire neural network [40, 41]. Moreover, CREB is also involved in sperm formation and the regulation of circadian rhythms [41].

Different studies have confirmed the important roles of CREB phosphorylation mainly in long-term learning and memory, involving procedures on Aplysia, flies, and rodents [4244]. In organotypic hippocampal slices, CREB phosphorylation continued to increase for 4 h during LTP maintenance, supporting the hypothesis that CREB plays an important role during the late phases of LTP [45]. Matsushita et al. [46] found that the PKA inhibitory peptide blocked both CREB phosphorylation and long-lasting LTP induction but not early LTP. Acute expression of active CREB caused an enhancement of both NMDA R-mediated synaptic responses and LTP, which was also accompanied by electrophysiological and morphological changes consistent with the generation of “silent synapses” [47]. The phosphorylation levels of ERK and CREB and the mRNA levels of CREB target genes (c-fos and Nr4a1) were significantly upregulated in the cerebral cortices of NR2B transgenic mice compared to their wild-type littermates, indicating that NR2B overexpression leads to the enhancement of specific protein phosphorylation in the brain [48]. CREB phosphorylation is a fundamental process of signaling cascades, which is connected with the subsequent protein synthesis and the formation of new dendrites. Additionally, the activation of CREB is an important regulator of BDNF-induced gene expression and plays a central role in mediating neurotrophin response in neurons [49].

The immediate early gene expression and synaptic protein synthesis

The phosphorylation of CREB, the rapid activation of immediate early gene (IEG) and protein synthesis are three factors that can induce LTP. Once the CREB phosphorylation is inhibited, IEG expression and protein synthesis are unable to proceed [50, 51]. IEG, as a transcription factor for the induction of late response genes, can bind to the nuclear DNA regulatory region through its products. The protein products of late response genes mainly include structural proteins, enzymes, ion channels, and neurotransmitters that participate in the regeneration of neurons and synaptic plasticity [52].

IEG includes zif268, c-fos, c-jun, c-myc and activity-regulated cytoskeleton-associated protein (Arc), which can link the short term signals to the long term changes. Among IEGs, the c-fos and Arc play key roles for the maintenance of LTP. Research has found that the increase in zif/268 expression was more highly correlated with LTP duration than with the magnitude of initial LTP [53]. In addition, the mRNA and protein expressions of c-fos related genes, including c-jun, junB, and junD, increased when the LTP was induced [5456]. zif268 and c-Fos displayed markedly different patterns of hippocampal and prefrontal expression, with zif268 being more closely linked to spatial learning [57]. The Arc mRNA can be transported into the dendrites and generate cytoskeleton associated proteins in a few minutes after being highly stimulated, regulating the structural synaptic plasticity [58].

Long-term memory was considered to be mediated by protein synthesis-dependent, late-phase LTP. Two secreted proteins, tPA and BDNF, were thought to play important roles in the long-term memory. tPA, a major product of the IEG, is a serine protein kinase in mammals, which can decompose the plasminogen to plasmin. The tPA knockout mice appeared to have a selective impairment of hippocampal LTP induction, whereas the tPA-overexpression mice exhibited enhanced LTP. Moreover, tPA also participates in anxiety-related behavior, spatial memory and the induction of cerebellar motor memory [59]. Pang et al. [60] reported that tPA, by activating the extracellular protease plasmin, converted the precursor proBDNF to the mature BDNF (mBDNF) and that such conversion was critical for L-LTP expression in the hippocampus.


The regulation of NMDAR in learning and memory has been well-recognized by neurobiologists. The neural basis of learning and memory is synaptic plasticity. LTP is an indispensable model for studying the mechanism of NMDAR-dependent learning and memory. So far, the molecules involved in the NMDAR signaling pathway, including calcium ions, PSD-95, CaMK II, PKA, MAPK, CREB, and IEG, have been confirmed to be closely connected with LTP and synaptic plasticity. However, the relationship between NMDAR and other receptors, such as dopamine receptors, GABA receptors, and mGluRs, among others, remains to be studied. Other factors, including aging, hypoxia, ischemia, lead poisoning, and microwave radiation, among other factors, on memory and their mechanisms have not been fully elucidated. We believe the application of new technical methods will better elucidate the mechanism of learning and memory.


In summary, NMDAR, as an important glutamate receptor, has been proven to be closely related to LTP, learning and memory, and the development of neural plasticity. Key molecules connected with the NMDAR signaling pathway, such as calcium ions, PSD-95, CaMK II, PKA, MAPK, CREB and IEG, participate in the formation of learning and memory and synaptic plasticity. The main process includes the activation of NMDAR and the influx of calcium, the bridging roles of PSD-95 in postsynaptic plasticity, the autophosphorylation of CaMK II and its role in learning and memory, the production of cAMP and the activation of PKA and MAPK, the phosphorylation of CREB and its regulatory roles and IEG expression and synaptic protein synthesis. The competition of the above process requires the precise regulation of every molecule in the NMDAR connected signaling pathway. Therefore, the research on the key molecules connected with the NMDAR signaling pathway plays an irreplaceable role in revealing the mechanism of learning and memory and synaptic plasticity.



a-postsynaptic amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor


Activity-regulated cytoskeleton-associated protein


Brain-derived neurotrophic factor


Cyclic adenosine monophosphate


Calcium/calmodulin-dependent protein kinase II




CaM associated serine kinase


cAMP responsive element binding protein


Extracellular signal-regulated protein kinase


Immediate early gene


Long-term potentiation


Mitogen-activated protein kinase


Metabotropic glutamate receptor


N-methyl-D-aspartic acid receptor


Protein kinase A


Postynaptic density 95


Protein phosphatase 1


Tissue plasminogen activator


Voltage-gated calcium channel


  1. Citri A, Malenka RC. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology. 2008;33:18–41.

  2. Brigman JL, Wright T, Talani G, Prasad-Mulcare S, Jinde S, Seabold GK, et al. Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J Neurosci. 2010;30:4590–600.

    Article  CAS  PubMed Central  Google Scholar 

  3. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 2010;63:405–96.

  4. Zhang S, Jin Y, Liu X, Yang L, Ge ZJ, Wang H, et al. Methamphetamine modulates glutamatergic synaptic transmission in rat primary cultured hippocampal neurons. Brain Res. 2014;1582:1–11.

    Article  CAS  PubMed  Google Scholar 

  5. Delaney AJ, Sedlak PL, Autuori E, Power JM, Sah P. Synaptic NMDA receptors in basolateral amygdala principal neurons are triheteromeric proteins: physiological role of GluN2B subunits. J Neurophysiol. 2013;109:1391–402.

    Article  CAS  PubMed  Google Scholar 

  6. Grienberger C, Konnerth A. Imaging calcium in neurons. Neuron. 2012;73:862–85.

    Article  CAS  PubMed  Google Scholar 

  7. Sanna PP, Cammalleri M, Berton F, Simpson C, Lutjens R, Bloom FE, et al. 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. 2002;22:3359–65.

    CAS  PubMed  Google Scholar 

  8. Sanderson JL, Gorski JA, Dell'Acqua ML.NMDA Receptor-Dependent LTD Requires Transient Synaptic Incorporation of Ca2+-Permeable AMPARs Mediated by AKAP150-Anchored PKA and Calcineurin. Neuron. 2016;89:1000-15.

  9. Sobczyk A, Scheuss V, Svoboda K. NMDA receptor subunit-dependent [Ca2+] signaling in individual hippocampal dendritic spines. J Neurosci. 2005;25:6037–46.

    Article  CAS  PubMed  Google Scholar 

  10. Bloodgood BL, Sabatini BL. Nonlinear regulation of unitary synaptic signals by CaV(2.3) voltage-sensitive calcium channels located in dendritic spines. Neuron. 2007;53:249–60.

  11. Nevian T, Sakmann B. Spine Ca2+ signaling in spike-timing-dependent plasticity. J Neurosci. 2006;26:11001–13.

    Article  CAS  PubMed  Google Scholar 

  12. Catterall WA. Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol. 2000;16:521–55.

    Article  CAS  PubMed  Google Scholar 

  13. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC. Storage of spatial information by the maintenance mechanism of LTP. Science. 2006;313:1141–4.

    Article  CAS  PubMed  Google Scholar 

  14. Raveendran R, Devi Suma Priya S, Mayadevi M, Steephan M, Santhoshkumar TR, Cheriyan J, et al. Phosphorylation status of the NR2B subunit of NMDA receptor regulates its interaction with calcium/calmodulin-dependent protein kinase II. J Neurochem. 2009;110:92–105.

  15. Gardoni F, Schrama L, Kamal A, Gispen W, Cattabeni F, Di Luca M. Hippocampal synaptic plasticity involves competition between Ca2+/calmodulin-dependent protein kinase II and postsynaptic density 95 for binding to the NR2A subunit of the NMDA receptor. J Neurosci. 2001;21:1501–9.

    CAS  PubMed  Google Scholar 

  16. Lim IA, Merrill MA, Chen Y, Hell JW. Disruption of the NMDA receptor-PSD-95 interaction in hippocampal neurons with no obvious physiological short-term effect. Neuropharmacology. 2003;45:738–54.

    Article  CAS  PubMed  Google Scholar 

  17. El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS. PSD-95 involvement in maturation of excitatory synapses. Science. 2000;290:1364–8.

    CAS  PubMed  Google Scholar 

  18. Taft CE, Turrigiano GG. PSD-95 promotes the stabilization of young synaptic contacts. Philos Trans R Soc Lond B Biol Sci. 2013;369:20130134.

    Article  PubMed  Google Scholar 

  19. Nagura H, Ishikawa Y, Kobayashi K, Takao K, Tanaka T, Nishikawa K, et al. Impaired synaptic clustering of postsynaptic density proteins and altered signal transmission in hippocampal neurons, and disrupted learning behavior in PDZ1 and PDZ2 ligand binding-deficient PSD-95 knockin mice. Mol Brain. 2012;5:43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yoshii A, Constantine-Paton M. Postsynaptic localization of PSD-95 is regulated by all three pathways downstream of TrkB signaling. Front Synaptic Neurosci. 2014;6:6.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Fink CC, Meyer T. Molecular mechanisms of CaMKII activation in neuronal plasticity. Curr Opin Neurobiol. 2002;12:293–9.

    Article  CAS  PubMed  Google Scholar 

  22. Zhou X, Zheng F, Moon C, Schlüter OM, Wang H. Bi-directional regulation of CaMKIIα phosphorylation at Thr286 by NMDA receptors in cultured cortical neurons. J Neurochem. 2012;122:295–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sanhueza M, Lisman J. The CaMKII/NMDAR complex as a molecular memory. Mol Brain. 2013;6:10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lynch MA. Long-term potentiation and memory. Physiol Rev. 2004;84:87–136.

    Article  CAS  PubMed  Google Scholar 

  25. Gillespie JM, Hodge JJ. CASK regulates CaMKII autophosphorylation in neuronal growth, calcium signaling, and learning. Front Mol Neurosci. 2013;6:27.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Park CS, Elgersma Y, Grant SG, Morrison JH. alpha-Isoform of calcium-calmodulin-dependent protein kinase II and postsynaptic density protein 95 differentially regulate synaptic expression of NR2A- and NR2B-containing N-methyl-d-aspartate receptors in hippocampus. Neuroscience. 2008;151:43–55.

    Article  CAS  Google Scholar 

  27. Lisman J, Yasuda R, Raghavachari S. Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci. 2012;13:169–82.

    CAS  PubMed  Google Scholar 

  28. Yamauchi T. Molecular mechanism of learning and memory based on the research for Ca2+/calmodulin-dependent protein kinase II. Yakugaku Zasshi. 2007;127:1173–97.

    Article  CAS  PubMed  Google Scholar 

  29. Yang Y, Takeuchi K, Rodenas-Ruano A, Takayasu Y, Bennett MVL, Zukin RS. Developmental switch in requirement for PKA RIIbeta in NMDA-receptor-dependent synaptic plasticity at Schaffer collateral to CA1 pyramidal cell synapses. Neuropharmacology. 2009;56:56–65.

    Article  CAS  PubMed  Google Scholar 

  30. Yasuda H, Barth AL, Stellwagen D, Malenka RC. A developmental switch in the signaling cascades for LTP induction. Nat Neurosci. 2002;6:15–6.

    Article  Google Scholar 

  31. Skeberdis VA, Chevaleyre V, Lau CG, Goldberg JH, Pettit DL, Suadicani SO, et al. Protein kinase A regulates calcium permeability of NMDA receptors. Nat Neurosci. 2006;9:501–10.

    Article  CAS  PubMed  Google Scholar 

  32. 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;88(5):615-26.

  33. Barco A, Alarcon JM, Kandel ER. Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell. 2002;108:689–703.

    Article  CAS  PubMed  Google Scholar 

  34. Patterson SL, Pittenger C, Morozov A, Martin KC, Scanlin H, Drake C, et al. Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron. 2001;32:123–40.

    Article  CAS  PubMed  Google Scholar 

  35. Mao LM, Tang QS, Wang JQ. Regulation of extracellular signal-regulated kinase phosphorylation in cultured rat striatal neurons. Brain Res Bull. 2009;78:328–34.

    Article  CAS  PubMed  Google Scholar 

  36. Jin SX, Arai J, Tian X, Kumar-Singh R, Feig LA. Acquisition of contextual discrimination involves the appearance of a RAS-GRF1/p38 mitogen-activated protein (MAP) kinase-mediated signaling pathway that promotes long term potentiation (LTP). J Biol Chem. 2013;288:21703–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Genoux D, Haditsch U, Knobloch M, Michalon A, Storm D, Mansuy IM. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature. 2002;418:970–75.

    Article  CAS  PubMed  Google Scholar 

  38. Malleret G, Haditsch U, Genoux D, Jones MW, Bliss T, Vanhoose AM, et al. Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell. 2001;104:675–86.

    Article  CAS  PubMed  Google Scholar 

  39. Sharma SK, Bagnall MW, Sutton MA, Carew TJ. Inhibition of calcineurin facilitates the induction of memory for sensitization in Aplysia: requirement of mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 2003;100:4861–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fijal K, Nowak E, Leskiewicz M, Budziszewska B, Filip M. Working memory deficits and alterations of ERK and CREB phosphorylation following withdrawal from cocaine self-administration. Pharmacol Rep. 2015;67:881–9.

    Article  CAS  PubMed  Google Scholar 

  41. Ortega-Martinez S. A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front Mol Neurosci. 2015;8:46.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Barco A, Bailey CH, Kandel ER. Common molecular mechanisms in explicit and implicit memory. J Neurochem. 2006;97:1520–33.

    Article  CAS  PubMed  Google Scholar 

  43. Moncada D, Viola H. Phosphorylation state of CREB in the rat hippocampus: a molecular switch between spatial novelty and spatial familiarity? Neurobiol Learn Mem. 2006;86:9–18.

    Article  CAS  PubMed  Google Scholar 

  44. Florian C, Mons N, Roullet P. CREB antisense oligodeoxynucleotide administration into the dorsal hippocampal CA3 region impairs long-but not short-term spatial memory in mice. Learn Mem. 2006;13:465–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Leutgeb JK, Frey JU, Behnisch T. Single cell analysis of activity-dependent cyclic AMP-responsive element-binding protein phosphorylation during long-lasting long-term potentiation in area CA1 of mature rat hippocampal-organotypic cultures. Neuroscience. 2005;131:601–10.

    Article  CAS  PubMed  Google Scholar 

  46. Matsushita M, Tomizawa K, Moriwaki A, Li ST, Terada H, Matsui H. A high-efficiency protein transduction system demonstrating the role of PKA in long-lasting long-term potentiation. J Neurosci. 2001;21:6000–7.

    CAS  PubMed  Google Scholar 

  47. Marie H, Morishita W, Yu X, Calakos N, Malenka RC. Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron. 2005;45:741–52.

    Article  CAS  PubMed  Google Scholar 

  48. Li C, Zhang N, Hu Y, Wang H. NR2B overexpression leads to the enhancement of specific protein phosphorylation in the brain. Brain Res. 2014;1588:127–34.

    Article  CAS  PubMed  Google Scholar 

  49. Tabuchi A. Synaptic plasticity-regulated gene expression: a key event in the long-lasting changes of neuronal function. Biol Pharm Bull. 2008;31:327–35.

    Article  CAS  PubMed  Google Scholar 

  50. Gooney M, Lynch MA. Long-term potentiation in the dentate gyrus of the rat hippocampus is accompanied by brain-derived neurotrophic factor-induced activation of TrkB. J Neurochem. 2001;77:1198–207.

    Article  CAS  PubMed  Google Scholar 

  51. Yin Y, Edelman GM, Vanderklish PW. The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci U S A. 2002;99:2368–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Galván EJ, Pérez-Rosello T, Gómez-Lira G, Lara E, Gutiérrez R, Barrionuevo G. Synapse-specific compartmentalization of signaling cascades for LTP induction in CA3 interneurons. Neuroscience. 2015;290:332–45.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Richardson CL, Tate WP, Mason SE, Lawlor PA, Dragunow M, Abraham WC. Correlation between the induction of an immediate early gene, zif/268, and long-term potentiation in the dentate gyrus. Brain Res. 1992;580:147–54.

    Article  CAS  PubMed  Google Scholar 

  54. Ranieri F, Podda MV, Riccardi E, Frisullo G, Dileone M, Profice P, et al. Modulation of LTP at rat hippocampal CA3-CA1 synapses by direct current stimulation. J Neurophysiol. 2012;107:1868–80.

    Article  CAS  PubMed  Google Scholar 

  55. Gass P, Fleischmann A, Hvalby O, Jensen V, Zacher C, Strekalova T, et al. Mice with a fra-1 knock-in into the c-fos locus show impaired spatial but regular contextual learning and normal LTP. Brain Res Mol Brain Res. 2004;130:16–22.

    Article  CAS  PubMed  Google Scholar 

  56. Abraham WC, Dragunow M, Tate WP. The role of immediate early genes in the stabilization of long-term potentiation. Mol Neurobiol. 1991;5:297–314.

    Article  CAS  PubMed  Google Scholar 

  57. Farina FR, Commins S. Differential expression of immediate early genes Zif268 and c-Fos in the hippocampus and prefrontal cortex following spatial learning and glutamate receptor antagonism. Behav Brain Res. 2016;307:194–8.

    Article  CAS  PubMed  Google Scholar 

  58. Qiu J, Dunbar DR, Noble J, Cairns C, Carter R, Kelly V, et al. Decreased Npas4 and Arc mRNA levels in the hippocampus of aged memory-impaired wild type but not memory preserved 11β-HSD1 deficient mice. J Neuroendocrinol. 2016; 28(1). doi: 10.1111/jne.12339.

  59. Benchenane K, Castel H, Boulouard M, Bluthé R, Fernandez-Monreal M, Roussel BD, et al. Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory. J Cell Sci. 2007;120:578–85.

    Article  CAS  PubMed  Google Scholar 

  60. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science. 2004;306:487–91.

    Article  CAS  PubMed  Google Scholar 

Download references




This manuscript was supported by the National Natural Science Foundation of China (61401497). The roles of the funding body on our manuscript mainly involved the background research, literature collection, and guidance of the experimental design.

Availability of data and material

Not applicable.

Authors’ contributions

HW carried out the review and drafted the manuscript. RYP critically revised the manuscript. Both authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Rui-Yun Peng.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, H., Peng, RY. Basic roles of key molecules connected with NMDAR signaling pathway on regulating learning and memory and synaptic plasticity. Military Med Res 3, 26 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: