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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 role of NMDA R was first identified in synaptic plasticity and has been extensively studied.

Some molecules, such as Ca 2, postsynaptic density 95 (PSD-95), calciumcalmodulin-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 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.

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 3 5.

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.

The aim of this review is to discuss the important processes connected with NMDAR dependent learning and memory.

Fig. 1 The regulation of molecules in the NMDAR signaling pathway on learning and memory.

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.

Memory Map 2004 Licence Key Full Size Image

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 Full size image.

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 -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 Mg 2 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 Mg 2 to become unbound from NMDAR, leading to the open state of the NMDAR channel and the subsequent influx of Ca 2, 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 Ca 2 concentration, however this reaction can be inhibited by the NMDAR antagonist AP-5 or extracellular Mg 2.

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.