P1‐016: Effects of specific nicotinic acetylcholine receptor agonists on hippocampal long‐term potentiation

One feature of Alzheimer's Disease (AD) is the deficit in cholinergic neurotransmission, which has led to the development and use of acetyl cholinesterase inhibitors for the treatment of memory impairment in AD patients. Currently, approaches selectively targeting specific nicotinic acetylcholine receptors (nAChR) are in clinical development for symptomatic treatment of AD. These are a4b2 nAChR and a7 nAChR agonists which are believed to enhance acetylcholine and glutamate neurotransmission, respectively. In order to get a better insight into the role of these two nAChRs in learning and memory, in this study, we investigated the effects of the a4b2 nAChR agonist TC-1827 and the a7 nAChR partial agonist SSR180711 on hippocampal long-term potentiation (LTP). LTP is a widely accepted cellular experimental model of memory formation, which can be divided into early LTP and late LTP being protein-synthesis independent and dependent, respectively. TC-1827 was found to increase early LTP in a bell-shaped dose dependent manner, but did not affect late LTP. In contrast, the a7 nAChR partial agonist SSR180711 showed enhancing effects on both early and late LTP in a bell-shaped manner. Furthermore, SSR180711 not only increased early LTP, but transferred it into late LTP, which was not found with the a4b2 nAChR agonist. In conclusion, this study demonstrates that TC-1827 increases only early LTP, whereas SSR180711 enhances early and late LTP and even transfers early into late LTP. Therefore, based on these findings it might be suggested that a7 nAChR (partial) agonists might exhibit stronger efficacy on memory improvement than a4b2 nAChR agonists.