LTM is distinguished from other forms of memory by its sensitivity to protein and mRNA synthesis inhibitors, demonstrating new
protein synthesis and altered gene activity to be essential for its formation. This is because the range of synaptic and neuronal plasticity required for LTM are facilitated physically modifications of both the synaptic and membrane complement of proteins1. This was demonstrated in Lymnaea, where the expression of new genes from the RPeD1 soma is required for LTM formation. Sangha at al. have shown that injection of the transcription blocker actinomycin D after an hour of cooling disrupted the reconsolidation of LTM2 and of the translation blocker Anisomycin 2.5 hours before training prevented the establishment of both ITM and LTM3. Ultimately, the ablation of the RPeD1 soma before conditioning prevented LTM formation, but not its retrieval if removed after consolidation4. More detailed studies have identified the specific genes that are active or up-regulated during LTM formation and found that they all play a part in facilitating more permanent forms of neural plasticity, such as LTP, that would perhaps serve as the engram. These genes are involved in intracellular kinase networks, synaptic function, transcriptional activation and repression, membrane receptors, etc. In the invertebrate models of aversive operant conditioning, the pathway for inducing memory formation is postulated as follows: Ca2+ influx through NMDA receptors triggers a signalling cascade that leads to the generation of cAMP and activation of protein kinase A (PKA), which phosphorylates mitogen-activated protein kinase pathway (MAKP) and cAMP-response element binding protein (CREB) to activate the transcription of plasticity-associated genes5. This pathway appears to be highly conserved across species in the formation of associative memory across aversive operant conditioning models. Inhibition of protein kinase C (PKC), MAKP and NMDA receptors have been shown to block LTM and in some cases ITM formation in Lymnaea6. These results were replicated in a negatively reinforced operant learning paradigm in Aplysia, where in vivo injections of PKC or PKA inhibitors7and MAPK inhibitors8 were also able to abolish LTM formation. LTM formation after aversive conditioning of Lymnaea aerial respiratory behaviour caused a significant increase in the expression of mitogen-activated protein kinase kinase 1 (MEKK1), a signalling molecules in the MAPK pathway, and the novel expression of the epsilon isoform of PKC9. Aversive operant conditioned Lymnaea exhibited an increase in CREB1 expression during consolidation of learning into LTM. The subsequent CREB-dependent up-regulation in the synthesis of presynaptic release mechanisms syntaxin-1 and dynamin-1 most likely facilitate the increased probability of presynaptic vesicle release and induction of synaptic plasticity10. CREB1 may
Igaz, Sangha, Scheibenstock, Lukowiak, 2003 3 Sangha S, Scheibenstock A, McComb C, Lukowiak K., 2003 4 Scheibenstock, 2002) 5 Robert Waltereit and Michael Weller Molecular Neurobiology Volume 27, Number 1, 99-106, DOI: 10.1385/MN:27:1:99 6 Rosenegger, Lukowiak, 2010 7 Michel, Green, Lyons, Learn. Mem. 2011. 18: 19-23 8 Michel, Green, Eskin, Lyons, Learn. Mem. 2011. 18: 108-117 9 Rosenegger D, Wright C, Lukowiak K: Mol Brain 2010, 3(9):1-17. 10 Guo CH, Senzel A, Li K, Feng ZP.
Eskin A. Rein K. were able to avoid the heated side of the chamber during training. Motro B. Perelman A. Mutants of dunce. in which the flies learn to remain in a particular portion of an enclosed chamber in order to avoid an increase in temperature if venturing into the "punished area". showed no memory after training18. as a CRE site is found upstream of the C/EBP gene11. R Wolf. Wolf R. 1985.de/uni-wuerzburg/volltexte/2003/419/pdf/Thesisgesamt. Hippocampal gene expression analysis in multi. Journal of comparative physiology A Sensory neural and behavioral physiology (1996)Volume: 179. but showed no avoidance in the memory test17. A new paradigm of operant conditioning in Drosophila14. Kandel. These cross-species similarities suggest that these processes are fundamental to memory formation. Lyons LC. which is known to activate transcription of downstream genes that give rise to the growth of new synaptic connections.and single-trial learning tasks in vertebrate models have identified similar up-regulations in many genes involved in synaptic transmission. A homolog of C/EBP. M Heisenberg 18 Mariath.pdf) 21 Igaz. which has lesions in the gene that codes for a cAMP-specific phosphodiesterase15.opus-bayern. an enzyme that is part of a family of serine-threonine kinases that in mammals have been implicated in the MAPK signalling cascade controlling synaptic plasticity and memory formation19. 2004. Zars. 1982 17 G Wustmann. In a paradigm where heat was used to condition Drosophila to move a platform. as several mutations that lead to abnormal cAMP levels impair learning in an operant conditioning task. cell signalling and cell-cell interactions after learning. LTM formation in Aplysia was correlated with increased C/EBP expression specifically localized to the nervous centres controlling feeding 12. Of particular interest is the ignorant gene coding for the p90 ribosomal S6 kinase (RSK). Raabe. Medina. microarray analysis of hippocampal RNA from trained rats showed increased expression of 14 genes involved in synaptic transmission and signalling.Levitan D. Mutant flies with spatial deletions of the gene are shown to be deficient in the heat box task20. After a single trial contextual fear training. Pages: 429-436
Byers 1981 Livingstone. Gazzaniga . Heisenberg M:. Issue: 3. K Rein. 2004
. has also been identified in Lymnaea13. Other forms of
The cognitive neurosciences By Michael S. Issue 10. 2001
Wustmann G.Charactertization of memories and ignorant (S6KII) mutants in operant conditioning in the heat box (http://www. who also have a reduced level of adenylyl cyclase activity. The cAMP system plays an especially critical role in Drosophila memory formation. Vianna. and rutabaga. Heisenberg 20 . including CaMKIIa and ERK2 (which are known to be involved in memory formation and consolidation) and synatxin-1 (which has already been identified in Lymnaea study to be up-regulated in a CREB-dependent manner during LTM consolidation)21. the amnesiac mutants. Pages 779-787 19 Putz. Izquierdo. Bekinschetein. Susswein AJ (2008) 13 Hatakeyama. Volume 31. Bertolucci.also mediate the cAMP-dependent regulation of a family of cAMP-regulated transcription factors known as CCAAT/enhancer-binding protein (C/EBP) . 1996 1. Green CL. which also has a lesion in the adenylyl cyclase system that makes it less active and decrease the levels of cAMP16. has been able to identify several genes involved in memory formation.
avoidance learning tasks such as Morris water maze and stone T-maze have induced similar effects in a large number of genes.
Cavallaro. 1996 25 Tonegawa. Finally.23. Activity-induced CREB phosphorylation and c-Fos expression were significantly reduced in transgenic mice lacking Ca2+ stimulated CaMKIV activity in the forebrain. including NMDA receptors. now evidence suggests that it might govern memory consolidation through synaptic changes via its regulation of protein synthesis in neurons. 2003 26 Tonegawa. 2000 24 McHugh. transgenic mice with inhibited forebrain ERK activation exhibited selective LTM impairment in contextual fear conditioning and protein synthesis-dependent portion of hippocampal L-LTP 26. 2002 Hall et al. correlated with impairments in the consolidation-retention phase but not the acquisition phase in LTM and induction of hippocampal L-LTP25. 2003
. The ERK pathway is known to be involved in the phosphorylation of several key transcription factors. synaptotagmins. Knockout of the obligatory NR subunit NR1 in CA1 pyramidal cells in young adult mice lead to impairments in spatial learning acquisitioning Morris water maze24 and a variety of other classical conditioning trials. C/EBPb transcription factor22. Knockout of several above mentioned genes in mice have produced marked deficiency in the acquisition and consolidation of LTM after operant learning tasks.