With the increased life expectancy in the modern societies, understanding the molecular background of age-dependent cognitive decline gain more and more relevance. MinK-related peptides (MIRPs or KCNEs) are conserved single-pass transmembrane proteins that associate with voltage-gated pore forming potassium channels (Kv). These Kv channels are heteromeric complexes that are active alone, however ancillary subunits of the MIRP/KCNE gene family modulate their fundamental properties. Both the Kv channels and the MIRP/KCNE family proteins show a broad expression including the nervous system. The C. elegans genome encodes 4 MIRP homolog proteins (
mps-1, -2, -3, -4). Previous studies showed that
mps-2 or
mps-3 is linked to increased sensitivity to Na+ ions. In addition, MPS-1, -2, -3 proteins were found to interact with the K+ ion-channel KVS-1 in the ADF neuron of C. elegans and influence the current characteristics of the ion-channel. In this study, we investigated the role of MIRP proteins in olfactory associative memory. We identified
mps-2, as the only member of the C. elegans homolog of the MiRP protein family that alters long-term memory in young adult worms without influencing the learning (acquisition) and short-term memory processes. The role of
mps-2 is general; deletion of the gene causes similar phenotype in different olfactory long-term memory assays. Furthermore, we established a long-term salt memory assay and demonstrated that loss of
mps-2 impairs also gustatory memory. We found that
mps-2 expression is up-regulated during long-term memory and in addition, in wild type worms the expression of the gene gradually decreases with age. In order to make a link between
mps-2 and age-dependent memory decline, we ectopically expressed
mps-2 in aged worms, which restored the impaired memory back to young animals performance. Finally, genetic epistasis and qPCR results show that
mps-2 acts downstream of the CREB homolog
crh-1 and upstream of voltage-gated potassium channels. Thus, MPS-2 may represent a novel component of long-term memory formation and may be responsible for age-dependent memory decline. Due to the functional conservation at the molecular level between C. elegans and vertebrates, our results will likely lead to fundamental advances on understanding molecular mechanisms of the age-dependent cognitive decline.