Dual Role of an mps-2/KCNE-Dependent Pathway in Long-Term Memory and Age-Dependent Memory Decline

• Published in: Current biology 2021-02, Vol.31 (3), p.527-539.e7
• Main Authors: Fenyves, Bank G., Arnold, Andreas, Gharat, Vaibhav G., Haab, Carmen, Tishinov, Kiril, Peter, Fabian, de Quervain, Dominique, Papassotiropoulos, Andreas, Stetak, Attila
• Format: Article
• Language: English
• Subjects: ageing; Animals; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; KCNE; kvs-3; kvs-4; long-term memory; Memory Disorders; Memory, Long-Term; mps-2; nhr-66; Potassium Channels, Voltage-Gated; voltage-gated ion-channel
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2020.10.069

Activity-dependent persistent changes in neuronal intrinsic excitability and synaptic strength are underlying learning and memory. Voltage-gated potassium (Kv) channels are potential regulators of memory and may be linked to age-dependent neuronal disfunction. MinK-related peptides (MiRPs) are conserved transmembrane proteins modulating Kv 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 Kv2.1/KVS-3 and Kv2.2/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. [Display omitted] •MPS-2/KCNE controls long-term associative memory•MPS-2 is in complex and acts through KVS-3 and KVS-4 voltage-gated K+ channels•Age-dependent memory decline is linked to MPS-2 expression levels•NHR-66 actively represses MPS-2 expression, controlling age-dependent memory decline Fenyves et al. report a conserved MPS-2/KVS-3/KVS-4 pathway essential for long-term associative memory in C. elegans. Furthermore, MPS-2 controls age-dependent memory decline being the target of a controlled repression mechanism mediated by NHR-66. These results provide a link between a conserved memory pathway and age-dependent memory decline.