N-methyl-D-aspartate receptor (NMDAR) function can be positively regulated by α calcium calmodulin kinase (αCaMKII) phosphorylation and by the transient activation of cyclin-dependent kinase 5 (Cdk5) through the positive regulator p25. Transport of the NR2B subunit to synaptic sites can be increased by overexpressing the motor protein KIF17. Calpain, possibly modulated by Cdk5, downregulates NR2B by proteolysis. The β3 subunit of voltage-gated calcium channel (VGCC) and the nociceptin receptor ORL1 also negatively regulate NMDAR expression or function by unknown mechanisms. Calcium influx through NMDARs activates αCaMKII, which in turn positively regulates NMDAR and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) function, contributing to the induction and expression of long-term potentiation (LTP), respectively. In addition, neuronal calcium concentration can be regulated by Na⁺/Ca²⁺ exchangers (NCXs), which extrude Ca²⁺ from neurons. Calcium/calmodulin (CaM) activates downstream kinases and phosphatases: it activates adenylyl cyclase (AC) to produce cAMP, which activates protein kinase A (PKA) and eventually regulates cyclic-AMP response-element-binding protein (CREB) activity in the nucleus. By phosphorylating inhibitor-1 (I-1), PKA can antagonize the action of protein phosphatase 1 (PP1), which is activated by the calcium/CaM-activated phosphatase calcineurin (CN). CaM also activates calcium CaM kinase kinase (CaMKK), which in turn activates calcium/CaM kinase IV (CaMKIV), another positive regulator of transcription. Activation of TrkB by brain-derived neurotrophic factor (BDNF) triggers the mitogen-activated protein kinase (MAPK) signalling pathway and ultimately regulates transcription. Sharp and blunted arrows represent positive and negative regulation, respectively. tPA/PS, tissue-type plasminogen activator/plasmin; PDE, phosphodiesterase.

Memory enhancements have been achieved by manipulating signalling largely in four different domains of the synapse. First, in the presynaptic axonal terminal; molecular manipulations that increased glutamate release have been shown to enhance learning and memory (L&M). Second, at the postsynaptic site; manipulations that upregulate the levels or enhance the function of N-methyl-D-aspartate receptors (NMDAR) either directly (through KIF17 for example, or by phosphorylation through calcium calmodulin kinase II (CaMKII) or p25/Cdk5) or indirectly (for example through deletion of Ca_vβ3 or D-amino-acid oxidase (DAAO)) have been shown to enhance L&M. Third, in the nucleus through the postsynaptic transcription factor cyclic-AMP response-element-binding protein (CREB); actions of several kinases/phosphatases, that are regulated by calcium influx mainly through NMDAR, converge on CREB. De novo gene expression contributes to the stabilization and consolidation of synaptic plasticity and memory. Fourth, by structural changes at the synapse; molecules that participate in key structural changes involved in memory, such as the formation of new synapses, can be manipulated to enhance memory. Manipulations of structural molecules such as heparin-binding growth-associated molecule (HB-GAM) and telencephalin (TLCN) result in L&M enhancement. The molecules marked with an asterisk (*) are examples of genes for which bidirectional manipulations lead to deficits and enhancements in L&M. For example, inhibition of calcineurin (CN) enhances memory whereas overexpression of CN impaired L&M (see text for details). In addition to NMDAR, manipulations of other modulatory neurotransmitter systems such as serotonin, γ-aminobutyric acid (GABA) and histamine can enhance memory. Glial proteins (S100 calcium-binding protein5(S100b) and DAAO) also play active roles in L&M. Sharp and blunted arrows represent positive and negative regulation, respectively. Either the overexpression or activation of molecules in green, or the deletion or inhibition of molecules in red enhance L&M. HDC, histidine decarboxylase; NCX2, Na⁺/Ca²⁺ exchanger type 2; ORL1, nociceptin receptor; PKA, protein kinase A; PP1, protein phosphatase 1; tPA, tissue-type plasminogen activator; 5-HT₃R, 5-HT₃ receptor.

The activity of cyclic-AMP response-element-binding protein (CREB) is regulated by phosphorylation or by molecular interactions. Protein kinase A (PKA), calcium calmodulin kinase IV (CaMKIV) and ribosomal S6 kinase (RSK) (activated by mitogen-activated protein (MAPK)) phosphorylate CREB at serine 133, whereas protein phosphatase-1 (PP1) dephosphorylates CREB. Another phosphatase, calcineurin (CN, also called PP2B) indirectly inhibits CREB function. Phosphorylated CREB recruits the CREB-binding protein (CBP) and activates the transcription of immediate early genes (IEGs) such as c-fos, Zif268 and C/EBPs (CCAAT/enhancer-binding protein). C/EBPs themselves function as transcription factors activating or inhibiting the expression of another group of genes (late-response genes). Transcriptional activity of CREB can be repressed by activating transcription factor 4 (ATF4), which is translationally regulated by the αsubunit of elongation factor 2 (eIF2α). Inhibition of eIF2α phosphorylation by GCN2 (general control non-depressible 2) reduces the translation of ATF4 mRNA and subsequently enhances CREB-dependent gene expression and learning and memory. ATF4 is thought to compete with CREB to bind to CRE and other transcriptional components including CBP. Sharp and blunted arrows represent positive and negative regulation, respectively. CaMKK, CaMK kinase.