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

Bank G Fenyves; Andreas Arnold; Vaibhav G Gharat; Carmen Haab; Kiril Tishinov; Fabian Peter; Dominique de Quervain; Andreas Papassotiropoulos; Attila Stetak

doi:10.1016/j.cub.2020.10.069

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

Curr Biol. 2021 Feb 8;31(3):527-539.e7. doi: 10.1016/j.cub.2020.10.069. Epub 2020 Nov 30.

Authors

Bank G Fenyves¹, Andreas Arnold², Vaibhav G Gharat², Carmen Haab³, Kiril Tishinov⁴, Fabian Peter², Dominique de Quervain⁵, Andreas Papassotiropoulos⁶, Attila Stetak⁷

Affiliations

¹ Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Division of Molecular Neuroscience, Department of Psychology, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Department of Molecular Biology, Semmelweis University, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
² Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Division of Molecular Neuroscience, Department of Psychology, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland.
³ Division of Molecular Neuroscience, Department of Psychology, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland.
⁴ Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
⁵ Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Division of Cognitive Neuroscience, Department of Psychology, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; University Psychiatric Clinics, University of Basel, Wilhelm Klein-Strasse 27, 4055 Basel, Switzerland.
⁶ Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Division of Molecular Neuroscience, Department of Psychology, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Biozentrum, Life Sciences Training Facility, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland; University Psychiatric Clinics, University of Basel, Wilhelm Klein-Strasse 27, 4055 Basel, Switzerland.
⁷ Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Division of Molecular Neuroscience, Department of Psychology, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; University Psychiatric Clinics, University of Basel, Wilhelm Klein-Strasse 27, 4055 Basel, Switzerland. Electronic address: a.stetak@unibas.ch.

PMID: 33259792
DOI: 10.1016/j.cub.2020.10.069

Abstract

Activity-dependent persistent changes in neuronal intrinsic excitability and synaptic strength are underlying learning and memory. Voltage-gated potassium (K_v) 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_v 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_v2.1/KVS-3 and K_v2.2/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.

Keywords: Caenorhabditis elegans; KCNE; ageing; kvs-3; kvs-4; long-term memory; mps-2; nhr-66; voltage-gated ion-channel.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Caenorhabditis elegans / genetics
Caenorhabditis elegans / metabolism
Caenorhabditis elegans Proteins / genetics
Caenorhabditis elegans Proteins / metabolism
Memory Disorders*
Memory, Long-Term*
Potassium Channels, Voltage-Gated

Substances

Caenorhabditis elegans Proteins
Potassium Channels, Voltage-Gated

Grants and funding

P40 OD010440/OD/NIH HHS/United States