creB, LtP, and long-term memory

One of the biochemical processes include in the maintenance of L-LTP that is also implicated in various learning models is the modification of gene expression through the cyclic AMP second messenger system. The activated catalytic subunit of protein kinase A translocates to the nucleus where it phosphorylates a transcription factor which binds to cAMP response parts CREs in upstream regions of genes regulated through cAMP. The transcription factor is termed cAMP response element binding protein CREB. When it is phosphorylated CREB connect to cre and this engages the other elements required for transcription shown in the Figure. CREB can also be phosphorylated through calcium–calmodulin-dependent kinases for instance CaMKIV that will be activated by Ca²⁺ entry through NMDA receptors or any other mechanism which increases cytoplasmic calcium concentration. The CREB-mediated gene transcription is controlled in at least two ways:

- By protein phosphatases which are activated through the calcium-dependent protein calci- neurin

- By repressor proteins termed cAMP response component modulators (CREMs) which bind to cres and so prevent CREBs from doing so

Figure: Cyclic AMP response element binding protein (CREB) modulation of gene transcription. cre, cyclic AMP response element; CREM, cAMP response element modulator; CaMKIV, calcium–calmodulin-dependent kinase  IV; PKA, protein kinase  A; PPI, protein phosphatase I.

Considerable evidence suggests which CREB is implicated in long-term memory in a number of several learning models: procedural learning in an Aplysia marine snail odor discrimination learning in the fruit-fly Drosophila and various kind of learning in mammals. For instance, transgenic mice which lack two of the three CREB isoforms are impaired in three dissimilar tasks which depend on the hippocampus including the Morris water maze and fear conditioning which requires the amygdala. LTP is impaired through protein kinase and inhibitors and in CREB-deficient mice. Selectively deleting neurons overexpressing CREB in the lateral amygdale, but not a same proportion of randomly selected neurons, abolished fear memory in mice.