<P> Late LTP is induced by changes in gene expression and protein synthesis brought about by the persistent activation of protein kinases activated during E-LTP, such as MAPK . In fact, MAPK--specifically the extracellular signal - regulated kinase (ERK) subfamily of MAPKs--may be the molecular link between E-LTP and L - LTP, since many signaling cascades involved in E-LTP, including CaMKII and PKC, can converge on ERK . Recent research has shown that the induction of L - LTP can depend on coincident molecular events, namely PKA activation and calcium influx, that converge on CRTC1 (TORC1), a potent transcriptional coactivator for cAMP response element binding protein (CREB). This requirement for a molecular coincidence accounts perfectly for the associative nature of LTP, and, presumably, for that of learning . </P> <P> Upon activation, ERK may phosphorylate a number of cytoplasmic and nuclear molecules that ultimately result in the protein synthesis and morphological changes observed in L - LTP . These cytoplasmic and nuclear molecules may include transcription factors such as CREB . ERK - mediated changes in transcription factor activity may trigger the synthesis of proteins that underlie the maintenance of L - LTP . One such molecule may be protein kinase Mζ (PKMζ), a persistently active kinase whose synthesis increases following LTP induction . PKMζ is an atypical isoform of PKC that lacks a regulatory subunit and thus remains constitutively active . Unlike other kinases that mediate LTP, PKMζ is active not just in the first 30 minutes following LTP induction; rather, PKMζ becomes a requirement for LTP maintenance only during the late phase of LTP . PKMζ thus appears important for the persistence of memory and would be expected to be important in the maintenance of long - term memory . Indeed, administration of a PKMζ inhibitor into the hippocampus of the rat results in retrograde amnesia with intact short - term memory; PKMζ does not play a role in the establishment of short - term memory . PKMζ has recently been shown to underlie L - LTP maintenance by directing the trafficking and reorganization of proteins in the synaptic scaffolding that underlie the expression of L - LTP . Even more recently, transgenic mice lacking PKMζ demonstrate normal LTP, questioning the necessity of PKMζ . </P> <P> The long - term stabilization of synaptic changes is also determined by a parallel increase of pre - and postsynaptic structures such as axonal bouton, dendritic spine and postsynaptic density . On the molecular level, an increase of the postsynaptic scaffolding proteins PSD - 95 and Homer1c has been shown to correlate with the stabilization of synaptic enlargement . </P> <P> The identities of only a few proteins synthesized during L - LTP are known . Regardless of their identities, it is thought that they contribute to the increase in dendritic spine number, surface area, and postsynaptic sensitivity to neurotransmitter associated with L - LTP expression . The latter may be brought about in part by the enhanced synthesis of AMPA receptors during L - LTP . Late LTP is also associated with the presynaptic synthesis of synaptotagmin and an increase in synaptic vesicle number, suggesting that L - LTP induces protein synthesis not only in postsynaptic cells, but in presynaptic cells as well . As mentioned previously, for postsynaptic LTP induction to result in presynaptic protein synthesis, there must be communication from the postsynaptic to the presynaptic cell . This may occur via the synthesis of a retrograde messenger, discussed later . </P>

One factor that may lead to long-term potentiation is