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WIREs Syst Biol Med
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Mechanisms of memory enhancement

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The ongoing quest for memory enhancement is one that grows necessary as the global population increasingly ages. The extraordinary progress that has been made in the past few decades elucidating the underlying mechanisms of how long‐term memories are formed has provided insight into how memories might also be enhanced. Capitalizing on this knowledge, it has been postulated that targeting many of the same mechanisms, including CREB activation, AMPA/NMDA receptor trafficking, neuromodulation (e.g., via dopamine, adrenaline, cortisol, or acetylcholine) and metabolic processes (e.g., via glucose and insulin) may all lead to the enhancement of memory. These and other mechanisms and/or approaches have been tested via genetic or pharmacological methods in animal models, and several have been investigated in humans as well. In addition, a number of behavioral methods, including exercise and reconsolidation, may also serve to strengthen and enhance memories. By utilizing this information and continuing to investigate these promising avenues, memory enhancement may indeed be achieved in the future. WIREs Syst Biol Med 2013, 5:37–53. doi: 10.1002/wsbm.1196

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Figure 1.

Multiple memory systems as targets of memory enhancement. Memory consists of multiple stages and types. A number of different stages (in blue) are involved in acquiring, storing, and retrieving a memory. A number of cognitive disorders (in red) have symptoms that are associated with deficits in specific stages, while others may have deficits that are more general or unclear in nature (such as those in cognitive decline over aging). Long‐term memory can be subdivided into a number of different types which rely on different brain regions (in purple). Impairments of these different memories are also associated with different disorders. Putative memory enhancers may be associated with the improvement of a specific stage or memory type, which will therefore affect the clinical population that will receive therapeutic benefit. WM, working memory; STM, short‐term memory; LTM, long‐term memory. (Reprinted with permission from Ref 17. Copyright 1992 American Psychological Association). The use of APA information does not imply endorsement by APA.

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Figure 2.

Schematic representation of the CREB‐C/EBP pathway targeted for memory enhancement. A number of intracellular signal transduction pathways are activated upon learning by diverse stimuli, such as stress, neurotransmitters, growth factors and membrane depolarization, and lead to activation of the CREB‐C/EBP pathway. Growth factors bind to and signal via dimerized receptor tyrosine kinase (RTK), which induces activation of both the Ras/Raf/mitogen‐activated protein kinase (MAPK)/MAP kinase kinase (MEK) pathway and the phosphatidylinositol 3‐kinase (PI3K)‐dependent pathway. Activation of these pathways recruit additional protein kinases, including p90 ribosomal S6 kinase (RSK2) and mitogen‐ and stress‐activated protein kinase (MSK) for the MAPK‐dependent pathway and Akt and p70S6 kinase (p70S6K) for the PI3K‐dependent pathway to catalyze phosphorylation of CREB (pCREB) in its Ser‐133 residue, which is an important step for its activation. Another route of CREB phosphorylation is through neurotransmitters binding to their receptors, through which they can couple cAMP by regulating adenylyl cyclase (AC) activity. cAMP recruits protein kinase A (PKA) as the main kinase for CREB phosphorylation. Phosphodiesterase (PDE) can catalyze the hydrolysis of cAMP and inhibit its signaling. Additionally, increases in intracellular Ca2+ influx through voltage‐ or ligand‐gated cation channels, such as voltage‐sensitive calcium channels (VSCCs) or NMDA receptors (NMDARs), can also lead to CREB phosphorylation via different calcium‐dependent protein kinases. Once phosphorylated, CREB recruits its transcription coactivator CREB‐binding protein (CBP) to promote transcription of CREB‐target genes, such as the immediate early gene, C/EBP. C/EBP, in turn, regulates a number of late‐response genes, for example, IGF‐II. Targeting any of these upstream pathways in a manner that leads to increased CREB or C/EBP activation, or targeting CREB‐C/EBP target genes (as in the case of IGF‐II), may in turn lead to long‐term memory enhancement. (Reprinted with permission from Ref 24. Copyright 2012 Elsevier)

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Figure 3.

Synaptic remodeling that occurs with learning. Presynaptic activity that occurs with learning or stimulation leads to a release of glutamate onto NMDA and AMPA receptors, which depolarizes the membrane. This leads to a number of intracellular changes, including activation of transcription factors, and translation of their downstream targets (Left Panel). These in turn lead to growth initiation, including protein synthesis (for example, of Arc), which then lead to the addition (Middle Panel) and stabilization (Right Panel) of new spines through insertion of new NMDA and AMPA receptors. Targeting synaptic remodeling mechanisms to increase receptor insertion may be an effective route for memory enhancement. (Reprinted with permission from Ref 48. Copyright 2007 Elsevier)

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