MinK-related peptides (MIRPs or KCNEs) are conserved transmembrane proteins that associate with voltage-gated pore forming potassium channels (Kv). In the brain, voltage-gated potassium channels play an important role in a multitude of neural functions including generation and regulation of LTP. However, the role of MIRPs in associative learning and memory, their regulation and connection to the age-dependent cognitive decline are currently unknown. Here we show that in C. elegans the KCNE homolog,
mps-2 is the sole member of the MiRP protein family that impairs aversive long-term memory (LTAM) in young adult worms. Furthermore, we demonstrate that
mps-2 expression is up-regulated during LTAM, it is the major downstream target of the canonical CREB pathway and CRH-1/CREB directly regulates increase of
mps-2 expression during LTAM, which later modulates the activity of Kv2.1/KVS-3 and Kv2.2/KVS-4 ion-channel oligomers. Thus, our results suggest that the canonical CMK-1/CRH-1 pathway is regulating long-term memory predominantly through transcriptional regulation of
mps-2 levels, which in turn modulates activity of specific Kv potassium channels. On the other hand, baseline expression of
mps-2 decreases with age in a CREB independent manner and ectopic temporal induction of
mps-2 levels in aged worms inhibits age-dependent memory decline. Promoter mapping revealed that a repressor element is essential to control age-dependent expression and using Y1H we identified the transcription factor that is responsible for inhibition of
mps-2 expression. Finally, deletion of the transcription factor or the binding element inhibits down-regulation of
mps-2 expression and memory decline with age. Thus, the MPS-2/KVS-3/KVS-4 pathway may represent a conserved molecular pathway essential for long-term memory, and involved in controlled decline of memory during ageing.