Reversal of age related learning deficiency by the vertebrate pituitary adenylate cyclase activating polypeptide (PACAP) in Lymnaea

Zsolt Pirger1,2, Souvik Naskar1, Zita Laszlo1,2, George Kemenes1, Laszlo Mark3, Dora Reglodi4, Ildiko Kemenes1. 1School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK, 2Comparative Neurobiological Research Group, Department of Experimental Zoology, Balaton Limnological Research Institute, Hungarian Academy of Sciences, Tihany, H-8237, Hungary, 3Department of Biochemistry and Medical Chemistry, Janos Szentagothai Research Center, University of Pecs, Pecs, H-7627, Hungary, 4Department of Anatomy, PTE-MTA “ Momentum” PACAP Team, University of Pecs, Pecs, H-7627, Hungary

The common pond snail (Lymnaea stagnalis) has been extensively used as a model system for studying the cellular and molecular mechanisms of associative learning and memory [1]. The main advantage of this system is that animals can learn after a single trial food reward conditioning and the memory can be recalled even after 3 weeks [2]. However this robust, “flash-bulb” like memory can only be induced in young adults (3-4 months old); aged snails (over 6 months) can not learn the association after only one training trial [3]. Recently we have shown that the homolog of the vertebrate PACAP and its receptors (PAC1-R, VPAC1 and VPAC2) exist in Lymnaea and PACAP activates the adenylate cyclase enzyme [4], just like in the vertebrate nervous system. We first tested the hypothesis that PACAP plays an important role in the formation of robust LTM after classical food-reward conditioning. Our earlier findings provided the first evidence that PACAP is both necessary and instructive for fast and robust memory formation after reward classical conditioning in young animals [5]. Here we tested the role of PACAP in learning in aged animals by looking at its effect on the formation of long-term memory after single trial appetitive conditioning. Our new results show that systemic injection of synthetic PACAP 1h before training boosts memory formation in old animals. Since PACAP is a highly conserved molecule, our results indicate that it has an important role in learning and memory in general and it can also be used as a memory “rejuvenating” agent during normal biological ageing.

[1] Kemenes 2012, In: Invertebrate Learning and Memory (eds. Menzel, R. and Benjamin, P.R.), Handbook of Behavioural Neuroscience (ed. Joseph P. Huston). Elsevier. In press.

[2] Alexander et al., J Neurobiol. 1984, 15(1):67-72.

[3] Audesirk et al., Behav Neural Biol. 1982, 36(4):379-90.

[4] Pirger et al., J Mol Neurosci. 2010, 42(3):464-71.

[5] Pirger et al., J Neurosci. 2010, 30(41):13766-73.

Funding: “Momentum” Program of the Hungarian Academy of Sciences (DR, ZP); BBSRC and MRC, UK (GK, ZP, SN, IK).