Activity-dependent persistent changes in neuronal intrinsic excitability and synaptic strength are underlying learning and memory. Voltage-gated potassium (K<sub>v</sub>) channels are potential regulators of memory and may be linked to age-dependent neuronal disfunction. MinK-related peptides (MiRPs) are conserved transmembrane proteins modulating K<sub>v</sub> channels; however, their possible role in the regulation of memory and age-dependent memory decline are unknown. Here, we show that, in C.elegans,
mps-2 is the sole member of the MiRP family that controls exclusively long-term associative memory (LTAM) in AVA neuron. In addition, we demonstrate that
mps-2 also plays a critical role in age-dependent memory decline. In young adult worms,
mps-2 is transcriptionally upregulated by CRH-1/cyclic AMP (cAMP)-response-binding protein (CREB) during LTAM, although the
mps-2 baseline expression is CREB independent and instead, during aging, relies on
nhr-66, which acts as an age-dependent repressor. Deletion of
nhr-66 or its binding element in the
mps-2 promoter prevents age-dependent transcriptional repression of
mps-2 and memory decline. Finally, MPS-2 acts through the modulation of the K<sub>v</sub>2.1/KVS-3 and K<sub>v</sub>2.2/KVS-4 heteromeric potassium channels. Altogether, we describe a conserved MPS-2/KVS-3/KVS-4 pathway essential for LTAM and also for a programmed control of physiological age-dependent memory decline.